E3 Ubiquitin Ligases: Structures, Biological Functions, Diseases, and Therapy

Abstract

E3 ubiquitin ligases are pivotal regulators within the ubiquitin–proteasome system, conferring specificity to protein ubiquitination and subsequent degradation, thereby maintaining cellular homeostasis. Their structural diversity allows for the precise control of vital processes, including the cell cycle, immune responses, and signal transduction, across various tissues. Despite their profound influence on physiology, a systematic understanding of how specific E3 ligases contribute to distinct disease pathogenesis and their translational potential remains incomplete. This review systematically delineates the classification and catalytic mechanisms of major E3 ligase families, including RING, HECT, and RBR types, and elaborates their pathological roles in driving carcinogenesis, cardiovascular remodeling, autoimmune dysregulation, metabolic syndrome, and neurodegenerative aggregation. We further synthesize recent advances in therapeutic modalities, from small-molecule inhibitors targeting ligases like MDM2 to novel strategies in targeted protein degradation, notably proteolysis-targeting chimeras (PROTACs) that hijack E3 machinery. By integrating mechanistic insights with emerging therapeutic landscapes, this work underscores the central role of E3 ligases in human diseases and provides a strategic framework for developing next-generation, mechanism-based therapeutics.

Keywords

cancer / E3 ubiquitin ligase / neurodegenerative diseases / PROTAC / targeted protein degradation

References

[1] A. Ciechanover, “Tracing the History of the Ubiquitin Proteolytic System: The Pioneering Article,” Biochemical and Biophysical Research Communications 387, no. 1 (2009): 1–10.

[2] A. Varshavsky, “The Early History of the Ubiquitin Field,” Protein Science 15, no. 3 (2006): 647–654.

[3] K. D. Wilkinson, “Ubiquitin: A Nobel Protein,” Cell 119, no. 6 (2004): 741–745.

[4] G. Cetin, S. Klafack, M. Studencka-Turski, E. Kruger, and F. Ebstein, “The Ubiquitin-Proteasome System in Immune Cells,” Biomolecules 11, no. 1 (2021): 60.

[5] A. D. Cowan and A. Ciulli, “Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons From Nature and the Laboratory,” Annual Review of Biochemistry 91 (2022): 295–319.

[6] P. Jevtic, D. L. Haakonsen, and M. Rape, “An E3 Ligase Guide to the Galaxy of Small-molecule-induced Protein Degradation,” Cell Chemical Biology 28, no. 7 (2021): 1000–1013.

[7] R. J. Deshaies and C. A. Joazeiro, “RING Domain E3 Ubiquitin Ligases,” Annual Review of Biochemistry 78 (2009): 399–434.

[8] L. Buetow and D. T. Huang, “Structural Insights Into the Catalysis and Regulation of E3 Ubiquitin Ligases,” Nature Reviews Molecular Cell Biology 17, no. 10 (2016): 626–642.

[9] Q. Yang, J. Zhao, D. Chen, and Y. Wang, “E3 ubiquitin Ligases: Styles, Structures and Functions,” Mol Biomed 2, no. 1 (2021): 23.

[10] C. Sampson, Q. Wang, W. Otkur, et al., “The Roles of E3 Ubiquitin Ligases in Cancer Progression and Targeted Therapy,” Clinical and translational medicine 13, no. 3 (2023): e1204.

[11] N. Liu, M. M. Lin, and Y. Wang, “The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases,” Molecular Neurobiology 60, no. 1 (2023): 247–263.

[12] L. Lu, C. Jifu, J. Xia, and J. Wang, “E3 ligases and DUBs Target Ferroptosis: A Potential Therapeutic Strategy for Neurodegenerative Diseases,” Biomedicine & Pharmacotherapy 175 (2024): 116753.

[13] K. Poels, W. G. Vos, E. Lutgens, and T. T. P. Seijkens, “E3 Ubiquitin Ligases as Immunotherapeutic Target in Atherosclerotic Cardiovascular Disease,” Frontiers in Cardiovascular Medicine 7 (2020): 106.

[14] Y. Jeong, A. R. Oh, Y. H. Jung, H. Gi, Y. U. Kim, and K. Kim, “Targeting E3 Ubiquitin Ligases and Their Adaptors as a Therapeutic Strategy for Metabolic Diseases,” Experimental & Molecular Medicine 55, no. 10 (2023): 2097–2104.

[15] A. E. Lin and T. W. Mak, “The Role of E3 Ligases in Autoimmunity and the Regulation of Autoreactive T Cells,” Current Opinion in Immunology 19, no. 6 (2007): 665–673.

[16] G. Madhukar, M. A. Haque, S. Khan, and J. J. Kim, “Danishuddin. E3 Ubiquitin Ligases and Their Therapeutic Potential in Disease Management,” Biochemical Pharmacology 236 (2025): 116875.

[17] R. Guo, F. Yang, and E. C. Cherney, “Small Molecule Targeted Protein Degradation via the UPS: Venturing Beyond E3 Substrate Receptors,” RSC Med Chem (2025). online ahead of print.

[18] A. Hanzl and G. E. Winter, “Targeted Protein Degradation: Current and Future Challenges,” Current Opinion in Chemical Biology 56 (2020): 35–41.

[19] X. Li, W. Pu, Q. Zheng, M. Ai, S. Chen, and Y. Peng, “Proteolysis-targeting Chimeras (PROTACs) in Cancer Therapy,” Molecular cancer 21, no. 1 (2022): 99.

[20] G. Sathe and G. P. Sapkota, “Proteomic Approaches Advancing Targeted Protein Degradation,” Trends in Pharmacological Sciences 44, no. 11 (2023): 786–801.

[21] J. M. Lee, H. M. Hammaren, M. M. Savitski, and S. H. Baek, “Control of Protein Stability by Post-translational Modifications,” Nature Communications 14, no. 1 (2023): 201.

[22] D. Popovic, D. Vucic, and I. Dikic, “Ubiquitination in Disease Pathogenesis and Treatment,” Nature Medicine 20, no. 11 (2014): 1242–1253.

[23] E. Oh, D. Akopian, and M. Rape, “Principles of Ubiquitin-Dependent Signaling,” Annual Review of Cell and Developmental Biology 34 (2018): 137–162.

[24] L. Deng, T. Meng, L. Chen, W. Wei, and P. Wang, “The Role of Ubiquitination in Tumorigenesis and Targeted Drug Discovery,” Signal Transduct Target Ther 5, no. 1 (2020): 11.

[25] R. H. Chen, Y. H. Chen, and T. Y. Huang, “Ubiquitin-mediated Regulation of Autophagy,” Journal of Biomedical Science 26, no. 1 (2019): 80.

[26] Y. Makaros, A. Raiff, R. T. Timms, et al., “Ubiquitin-independent Proteasomal Degradation Driven by C-degron Pathways,” Molecular Cell 83, no. 11 (2023): 1921–1935. e7.

[27] X. Chen, L. Jiang, Z. Zhou, et al., “The Role of Membrane-Associated E3 Ubiquitin Ligases in Cancer,” Frontiers in pharmacology 13 (2022): 928794.

[28] D. Komander, “The Emerging Complexity of Protein Ubiquitination,” Biochemical Society Transactions 37, no. Pt 5 (2009): 937–953.

[29] R. L. Welchman, C. Gordon, and R. J. Mayer, “Ubiquitin and Ubiquitin-Like Proteins as Multifunctional Signals,” Nature Reviews Molecular Cell Biology 6, no. 8 (2005): 599–609.

[30] A. Ciechanover and R. Ben-Saadon, “N-terminal Ubiquitination: More Protein Substrates Join in,” Trends in Cell Biology 14, no. 3 (2004): 103–106.

[31] R. Yau and M. Rape, “The Increasing Complexity of the Ubiquitin Code,” Nature Cell Biology 18, no. 6 (2016): 579–586.

[32] A. Lopata, A. Kniss, F. Lohr, V. V. Rogov, and V. Dotsch, “Ubiquitination in the ERAD Process,” International Journal of Molecular Sciences 21, no. 15 (2020): 5369.

[33] H. Oshiumi, “Recent Advances and Contradictions in the Study of the Individual Roles of Ubiquitin Ligases That Regulate RIG-I-Like Receptor-Mediated Antiviral Innate Immune Responses,” Frontiers in immunology 11 (2020): 1296.

[34] M. L. Matsumoto, K. E. Wickliffe, K. C. Dong, et al., “K11-linked Polyubiquitination in Cell Cycle Control Revealed by a K11 Linkage-specific Antibody,” Molecular Cell 39, no. 3 (2010): 477–484.

[35] K. E. Wickliffe, A. Williamson, H. J. Meyer, A. Kelly, and M. Rape, “K11-linked Ubiquitin Chains as Novel Regulators of Cell Division,” Trends in Cell Biology 21, no. 11 (2011): 656–663.

[36] H. Tsuchiya, F. Ohtake, N. Arai, et al., “In Vivo Ubiquitin Linkage-type Analysis Reveals That the Cdc48-Rad23/Dsk2 Axis Contributes to K48-Linked Chain Specificity of the Proteasome,” Molecular Cell 66, no. 4 (2017): 488–502. e7.

[37] A. J. Boughton, S. Krueger, and D. Fushman, “Branching via K11 and K48 Bestows Ubiquitin Chains With a Unique Interdomain Interface and Enhanced Affinity for Proteasomal Subunit Rpn1,” Structure (London, England) 28, no. 1 (2020): 29–43. e6.

[38] S. J. van Wijk, E. Fiskin, M. Putyrski, et al., “Fluorescence-based Sensors to Monitor Localization and Functions of Linear and K63-linked Ubiquitin Chains in Cells,” Molecular Cell 47, no. 5 (2012): 797–809.

[39] C. A. Castaneda, A. Chaturvedi, C. M. Camara, J. E. Curtis, S. Krueger, and D. Fushman, “Linkage-specific Conformational Ensembles of Non-canonical Polyubiquitin Chains,” Physical Chemistry Chemical Physics 18, no. 8 (2016): 5771–5788.

[40] Q. Zhou and J. Zhang, “K27-linked Noncanonic Ubiquitination in Immune Regulation,” J Leukoc Biol 111, no. 1 (2022): 223–235.

[41] M. A. Michel, K. N. Swatek, M. K. Hospenthal, and D. Komander, “Ubiquitin Linkage-Specific Affimers Reveal Insights Into K6-Linked Ubiquitin Signaling,” Molecular Cell 68, no. 1 (2017): 233–246. e5.

[42] S. F. Gao, B. Zhong, and D. Lin, “Regulation of T Helper Cell Differentiation by E3 Ubiquitin Ligases and Deubiquitinating Enzymes,” International Immunopharmacology 42 (2017): 150–156.

[43] M. J. Clague, S. Urbe, and D. Komander, “Breaking the Chains: Deubiquitylating Enzyme Specificity Begets Function,” Nature Reviews Molecular Cell Biology 20, no. 6 (2019): 338–352.

[44] I. Sahu and M. H. Glickman, “Proteasome in Action: Substrate Degradation by the 26S Proteasome,” Biochemical Society Transactions 49, no. 2 (2021): 629–644.

[45] A. d'Azzo, A. Bongiovanni, and T. Nastasi, “E3 ubiquitin Ligases as Regulators of Membrane Protein Trafficking and Degradation,” Traffic (Copenhagen, Denmark) 6, no. 6 (2005): 429–441.

[46] F. Dang, L. Nie, and W. Wei, “Ubiquitin Signaling in Cell Cycle Control and Tumorigenesis,” Cell Death and Differentiation 28, no. 2 (2021): 427–438.

[47] E. L. Jones, S. M. Laidlaw, and L. B. Dustin, “TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease,” Frontiers in immunology 12 (2021): 738473.

[48] E. Kevei, W. Pokrzywa, and T. Hoppe, “Repair or Destruction-an Intimate Liaison Between Ubiquitin Ligases and Molecular Chaperones in Proteostasis,” Febs Letters 591, no. 17 (2017): 2616–2635.

[49] A. Upadhyay, A. Amanullah, D. Chhangani, R. Mishra, and A. Mishra, “Selective Multifaceted E3 Ubiquitin Ligases Barricade Extreme Defense: Potential Therapeutic Targets for Neurodegeneration and Ageing,” Ageing Research Reviews 24, no. Pt B (2015): 138–159.

[50] L. M. Humphreys, P. Smith, Z. Chen, S. Fouad, and V. D'Angiolella, “The Role of E3 Ubiquitin Ligases in the Development and Progression of Glioblastoma,” Cell Death and Differentiation 28, no. 2 (2021): 522–537.

[51] L. Qi, X. Xu, and X. Qi, “The Giant E3 Ligase HUWE1 Is Linked to Tumorigenesis, Spermatogenesis, Intellectual Disability, and Inflammatory Diseases,” Frontiers in Cellular and Infection Microbiology 12 (2022): 905906.

[52] R. Tang, W. Y. Langdon, and J. Zhang, “Regulation of Immune Responses by E3 Ubiquitin Ligase Cbl-b,” Cellular Immunology 340 (2019): 103878.

[53] K. I. Nakayama and K. Nakayama, “Ubiquitin Ligases: Cell-cycle Control and Cancer,” Nature Reviews Cancer 6, no. 5 (2006): 369–381.

[54] A. V. Ivanov, H. Peng, V. Yurchenko, et al., “PHD Domain-mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing,” Molecular Cell 28, no. 5 (2007): 823–837.

[55] F. Zhai, J. Li, M. Ye, and X. Jin, “The Functions and Effects of CUL3-E3 Ligases Mediated Non-degradative Ubiquitination,” Gene 832 (2022): 146562.

[56] J. W. Harper and B. A. Schulman, “Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century beyond the F-Box Hypothesis,” Annual Review of Biochemistry 90 (2021): 403–429.

[57] N. Zheng and N. Shabek, “Ubiquitin Ligases: Structure, Function, and Regulation,” Annual Review of Biochemistry 86 (2017): 129–157.

[58] E. Bulatov and A. Ciulli, “Targeting Cullin-RING E3 Ubiquitin Ligases for Drug Discovery: Structure, Assembly and Small-molecule Modulation,” Biochemical Journal 467, no. 3 (2015): 365–386.

[59] J. N. Pruneda, P. J. Littlefield, S. E. Soss, et al., “Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared Among RING/U-box Ligases,” Molecular Cell 47, no. 6 (2012): 933–942.

[60] S. Hatakeyama, M. Yada, M. Matsumoto, N. Ishida, and K. I. Nakayama, “U Box Proteins as a New family of Ubiquitin-protein Ligases,” Journal of Biological Chemistry 276, no. 35 (2001): 33111–33120.

[61] H. B. Kamadurai, Y. Qiu, A. Deng, et al., “Mechanism of Ubiquitin Ligation and Lysine Prioritization by a HECT E3,” Elife 2 (2013): e00828.

[62] S. Lorenz, “Structural Mechanisms of HECT-type Ubiquitin Ligases,” Biological Chemistry 399, no. 2 (2018): 127–145.

[63] J. Sluimer and B. Distel, “Regulating the human HECT E3 Ligases,” Cellular and Molecular Life Sciences 75, no. 17 (2018): 3121–3141.

[64] K. K. Dove, B. Stieglitz, E. D. Duncan, K. Rittinger, and R. E. Klevit, “Molecular Insights Into RBR E3 Ligase Ubiquitin Transfer Mechanisms,” Embo Reports 17, no. 8 (2016): 1221–1235.

[65] D. E. Spratt, H. Walden, and G. S. Shaw, “RBR E3 Ubiquitin Ligases: New Structures, New Insights, New Questions,” Biochemical Journal 458, no. 3 (2014): 421–437.

[66] J. S. Brown, S. R. Amend, R. H. Austin, R. A. Gatenby, E. U. Hammarlund, and K. J. Pienta, “Updating the Definition of Cancer,” Molecular Cancer Research 21, no. 11 (2023): 1142–1147.

[67] X. Zhang, S. Linder, and M. Bazzaro, “Drug Development Targeting the Ubiquitin-Proteasome System (UPS) for the Treatment of Human Cancers,” Cancers (Basel) 12, no. 4 (2020): 902.

[68] D. Wang, L. Ma, B. Wang, J. Liu, and W. Wei, “E3 ubiquitin Ligases in Cancer and Implications for Therapies,” Cancer and Metastasis Reviews 36, no. 4 (2017): 683–702.

[69] Y. Zhao, J. Li, J. Chen, M. Ye, and X. Jin, “Functional Roles of E3 Ubiquitin Ligases in Prostate Cancer,” J Mol Med (Berl) 100, no. 8 (2022): 1125–1144.

[70] D. Senft, J. Qi, and Z. A. Ronai, “Ubiquitin Ligases in Oncogenic Transformation and Cancer Therapy,” Nature Reviews Cancer 18, no. 2 (2018): 69–88.

[71] H. Hou, D. Sun, and X. Zhang, “The Role of MDM2 Amplification and Overexpression in Therapeutic Resistance of Malignant Tumors,” Cancer cell international 19 (2019): 216.

[72] E. R. Watson, N. G. Brown, J. M. Peters, H. Stark, and B. A. Schulman, “Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division,” Trends in Cell Biology 29, no. 2 (2019): 117–134.

[73] L. K. Teixeira and S. I. Reed, “Ubiquitin Ligases and Cell Cycle Control,” Annual Review of Biochemistry 82 (2013): 387–414.

[74] M. P. Swaffer, A. W. Jones, H. R. Flynn, A. P. Snijders, and P. Nurse, “CDK Substrate Phosphorylation and Ordering the Cell Cycle,” Cell 167, no. 7 (2016): 1750–1761. e16.

[75] R. Suryadinata, M. Sadowski, and B. Sarcevic, “Control of Cell Cycle Progression by Phosphorylation of Cyclin-dependent Kinase (CDK) Substrates,” Bioscience Reports 30, no. 4 (2010): 243–255.

[76] L. F. Chang, Z. Zhang, J. Yang, S. H. McLaughlin, and D. Barford, “Molecular Architecture and Mechanism of the Anaphase-promoting Complex,” Nature 513, no. 7518 (2014): 388–393.

[77] F. Herzog, I. Primorac, P. Dube, et al., “Structure of the Anaphase-promoting Complex/Cyclosome Interacting With a Mitotic Checkpoint Complex,” Science 323, no. 5920 (2009): 1477–1481.

[78] Z. Zhou, M. He, A. A. Shah, and Y. Wan, “Insights Into APC/C: From Cellular Function to Diseases and Therapeutics,” Cell Div 11 (2016): 9.

[79] T. Listovsky, Y. S. Oren, Y. Yudkovsky, et al., “Mammalian Cdh1/Fzr Mediates Its Own Degradation,” Embo Journal 23, no. 7 (2004): 1619–1626.

[80] E. R. Kramer, N. Scheuringer, A. V. Podtelejnikov, M. Mann, and J. M. Peters, “Mitotic Regulation of the APC Activator Proteins CDC20 and CDH1,” Molecular Biology of the Cell 11, no. 5 (2000): 1555–1569.

[81] C. Lindon and J. Pines, “Ordered Proteolysis in Anaphase Inactivates Plk1 to Contribute to Proper Mitotic Exit in human Cells,” Journal of Cell Biology 164, no. 2 (2004): 233–241.

[82] W. Wang and M. W. Kirschner, “Emi1 preferentially Inhibits Ubiquitin Chain Elongation by the Anaphase-promoting Complex,” Nature Cell Biology 15, no. 7 (2013): 797–806.

[83] S. D. Cappell, K. G. Mark, D. Garbett, L. R. Pack, M. Rape, and T. Meyer, “EMI1 switches From Being a Substrate to an Inhibitor of APC/C(CDH1) to Start the Cell Cycle,” Nature 558, no. 7709 (2018): 313–317.

[84] G. Rodier, P. Coulombe, P. L. Tanguay, C. Boutonnet, and S. Meloche, “Phosphorylation of Skp2 Regulated by CDK2 and Cdc14B Protects It From Degradation by APC(Cdh1) in G1 Phase,” Embo Journal 27, no. 4 (2008): 679–691.

[85] A. Cerqueira, A. Martin, C. E. Symonds, et al., “Genetic Characterization of the Role of the Cip/Kip family of Proteins as Cyclin-dependent Kinase Inhibitors and Assembly Factors,” Molecular and Cellular Biology 34, no. 8 (2014): 1452–1459.

[86] D. Frescas and M. Pagano, “Deregulated Proteolysis by the F-box Proteins SKP2 and Beta-TrCP: Tipping the Scales of Cancer,” Nature Reviews Cancer 8, no. 6 (2008): 438–449.

[87] T. Kamura, T. Hara, S. Kotoshiba, et al., “Degradation of p57Kip2 Mediated by SCFSkp2-dependent Ubiquitylation,” PNAS 100, no. 18 (2003): 10231–10236.

[88] D. M. Koepp, L. K. Schaefer, X. Ye, et al., “Phosphorylation-dependent Ubiquitination of Cyclin E by the SCFFbw7 Ubiquitin Ligase,” Science 294, no. 5540 (2001): 173–177.

[89] K. Klotz, D. Cepeda, Y. Tan, D. Sun, O. Sangfelt, and C. Spruck, “SCF(Fbxw7/hCdc4) Targets Cyclin E2 for Ubiquitin-dependent Proteolysis,” Experimental Cell Research 315, no. 11 (2009): 1832–1839.

[90] M. Welcker, A. Orian, J. Jin, et al., “The Fbw7 Tumor Suppressor Regulates Glycogen Synthase Kinase 3 Phosphorylation-dependent c-Myc Protein Degradation,” PNAS 101, no. 24 (2004): 9085–9090.

[91] S. Y. Kim, A. Herbst, K. A. Tworkowski, S. E. Salghetti, and W. P. Tansey, “Skp2 regulates Myc Protein Stability and Activity,” Molecular Cell 11, no. 5 (2003): 1177–1188.

[92] J. Berthold, K. Schenkova, S. Ramos, et al., “Characterization of RhoBTB-dependent Cul3 Ubiquitin Ligase Complexes–evidence for an Autoregulatory Mechanism,” Experimental Cell Research 314, no. 19 (2008): 3453–3465.

[93] Z. Chen, K. Wang, C. Hou, et al., “CRL4B(DCAF11) E3 ligase Targets p21 for Degradation to Control Cell Cycle Progression in human Osteosarcoma Cells,” Scientific Reports 7, no. 1 (2017): 1175.

[94] S. Wei, J. Xing, J. Chen, et al., “DCAF13 inhibits the p53 Signaling Pathway by Promoting p53 Ubiquitination Modification in Lung Adenocarcinoma,” Journal of Experimental & Clinical Cancer Research 43, no. 1 (2024): 3.

[95] A. Wilkins, Q. Ping, and C. L. Carpenter, “RhoBTB2 is a Substrate of the Mammalian Cul3 Ubiquitin Ligase Complex,” Genes & development 18, no. 8 (2004): 856–861.

[96] D. Banks, M. Wu, L. A. Higa, et al., “L2DTL/CDT2 and PCNA Interact With p53 and Regulate p53 Polyubiquitination and Protein Stability Through MDM2 and CUL4A/DDB1 Complexes,” Cell Cycle 5, no. 15 (2006): 1719–1729.

[97] B. L. Mouery, E. M. Baker, L. Mei, et al., “APC/C Prevents a Noncanonical Order of Cyclin/CDK Activity to Maintain CDK4/6 Inhibitor-induced Arrest,” PNAS 121, no. 30 (2024): e2319574121.

[98] H. T. Ma, Y. H. Tsang, M. Marxer, and R. Y. Poon, “Cyclin A2-cyclin-dependent Kinase 2 Cooperates With the PLK1-SCFbeta-TrCP1-EMI1-anaphase-promoting Complex/Cyclosome Axis to Promote Genome Reduplication in the Absence of Mitosis,” Molecular and Cellular Biology 29, no. 24 (2009): 6500–6514.

[99] K. Fujimitsu, M. Grimaldi, and H. Yamano, “Cyclin-dependent Kinase 1-dependent Activation of APC/C Ubiquitin Ligase,” Science 352, no. 6289 (2016): 1121–1124.

[100] Z. Tang, B. Li, R. Bharadwaj, et al., “APC2 Cullin Protein and APC11 RING Protein Comprise the Minimal Ubiquitin Ligase Module of the Anaphase-promoting Complex,” Molecular Biology of the Cell 12, no. 12 (2001): 3839–3851.

[101] N. Zheng, B. A. Schulman, L. Song, et al., “Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF Ubiquitin Ligase Complex,” Nature 416, no. 6882 (2002): 703–709.

[102] H. Yu, “Cdc20: A WD40 Activator for a Cell Cycle Degradation Machine,” Molecular Cell 27, no. 1 (2007): 3–16.

[103] X. Qiao, L. Zhang, A. M. Gamper, T. Fujita, and Y. Wan, “APC/C-Cdh1: From Cell Cycle to Cellular Differentiation and Genomic Integrity,” Cell Cycle 9, no. 19 (2010): 3904–3912.

[104] D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The next Generation,” Cell 144, no. 5 (2011): 646–674.

[105] A. Amin, P. A. Karpowicz, T. E. Carey, et al., “Evasion of Anti-growth Signaling: A Key Step in Tumorigenesis and Potential Target for Treatment and Prophylaxis by Natural Compounds,” Seminars in Cancer Biology 35, no. Suppl (2015): S55–S77.

[106] L. H. Gallo, J. Ko, and D. J. Donoghue, “The Importance of Regulatory Ubiquitination in Cancer and Metastasis,” Cell Cycle 16, no. 7 (2017): 634–648.

[107] R. Sever and J. S. Brugge, “Signal Transduction in Cancer,” Cold Spring Harbor perspectives in medicine 5, no. 4 (2015): a006098.

[108] K. T. Bieging, S. S. Mello, and L. D. Attardi, “Unravelling Mechanisms of p53-mediated Tumour Suppression,” Nature Reviews Cancer 14, no. 5 (2014): 359–370.

[109] A. M. Bode and Z. Dong, “Post-translational Modification of p53 in Tumorigenesis,” Nature Reviews Cancer 4, no. 10 (2004): 793–805.

[110] C. Harakandi, L. Nininahazwe, H. Xu, et al., “Recent Advances on the Intervention Sites Targeting USP7-MDM2-p53 in Cancer Therapy,” Bioorganic Chemistry 116 (2021): 105273.

[111] M. Li, C. L. Brooks, F. Wu-Baer, D. Chen, R. Baer, and W. Gu, “Mono- versus Polyubiquitination: Differential Control of p53 Fate by Mdm2,” Science 302, no. 5652 (2003): 1972–1975.

[112] M. Wade, Y. C. Li, A. S. Matani, et al., “Functional Analysis and Consequences of Mdm2 E3 Ligase Inhibition in human Tumor Cells,” Oncogene 31, no. 45 (2012): 4789–4797.

[113] L. Nie, M. Sasaki, and C. G. Maki, “Regulation of p53 Nuclear Export Through Sequential Changes in Conformation and Ubiquitination,” Journal of Biological Chemistry 282, no. 19 (2007): 14616–14625.

[114] M. Wade, Y. V. Wang, and G. M. Wahl, “The p53 Orchestra: Mdm2 and Mdmx Set the Tone,” Trends in Cell Biology 20, no. 5 (2010): 299–309.

[115] C. J. Brown, S. Lain, C. S. Verma, A. R. Fersht, and D. P. Lane, “Awakening Guardian Angels: Drugging the p53 Pathway,” Nature Reviews Cancer 9, no. 12 (2009): 862–873.

[116] S. Valentini, G. Mele, M. Attili, et al., “Targeting the MDM2-MDM4 Interaction Interface Reveals an Otherwise Therapeutically Active Wild-type p53 in Colorectal Cancer,” Molecular Oncology 19, no. 8 (2025): 2412–2430.

[117] O. Karni-Schmidt, M. Lokshin, and C. Prives, “The Roles of MDM2 and MDMX in Cancer,” Annual Review of Pathology: Mechanisms of Disease 11, no. 1 (2016): 617–644.

[118] W. L. Gluck, M. M. Gounder, R. Frank, et al., “Phase 1 Study of the MDM2 Inhibitor AMG 232 in Patients With Advanced P53 Wild-type Solid Tumors or Multiple Myeloma,” Investigational New Drugs 38, no. 3 (2019): 831–843.

[119] L. Wang, G. He, P. Zhang, X. Wang, M. Jiang, and L. Yu, “Interplay Between MDM2, MDMX, Pirh2 and COP1: The Negative Regulators of p53,” Molecular Biology Reports 38, no. 1 (2010): 229–236.

[120] C. A. Corcoran, Y. Huang, and M. S. Sheikh, “The p53 Paddy Wagon: COP1, Pirh2 and MDM2 Are Found Resisting Apoptosis and Growth Arrest,” Cancer Biology & Therapy 3, no. 8 (2004): 721–725.

[121] J.-O. Jin, G. D. Lee, and S. H. Nam, “Sequential Ubiquitination of p53 by TRIM28, RLIM, and MDM2 in Lung Tumorigenesis,” Cell Death & Differentiation 28, no. 6 (2020): 1790–1803.

[122] D. Li, N. D. Marchenko, R. Schulz, et al., “Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in human Cancer Cells,” Molecular Cancer Research 9, no. 5 (2011): 577–588.

[123] P. Muller, R. Hrstka, D. Coomber, D. P. Lane, and B. Vojtesek, “Chaperone-dependent Stabilization and Degradation of p53 Mutants,” Oncogene 27, no. 24 (2008): 3371–3383.

[124] J. Wang, Q. Zhao, Q. Qi, et al., “Gambogic Acid-induced Degradation of Mutant p53 Is Mediated by Proteasome and Related to CHIP,” Journal of Cellular Biochemistry 112, no. 2 (2011): 509–519.

[125] F. A. Dick and S. M. Rubin, “Molecular Mechanisms Underlying RB Protein Function,” Nature Reviews Molecular Cell Biology 14, no. 5 (2013): 297–306.

[126] N. Dyson, “The Regulation of E2F by pRB-family Proteins,” Genes & development 12, no. 15 (1998): 2245–2262.

[127] D. Cobrinik, “Pocket Proteins and Cell Cycle Control,” Oncogene 24, no. 17 (2005): 2796–2809.

[128] S. Zhang, L. F. Valenzuela, E. Zatulovskiy, L. Mangiante, C. Curtis, and J. M. Skotheim, “The G(1)-S Transition Is Promoted by Rb Degradation via the E3 Ligase UBR5,” Science Advances 10, no. 43 (2024): eadq6858.

[129] Y. Wang, Z. Zheng, J. Zhang, et al., “A Novel Retinoblastoma Protein (RB) E3 Ubiquitin Ligase (NRBE3) Promotes RB Degradation and Is Transcriptionally Regulated by E2F1 Transcription Factor,” Journal of Biological Chemistry 290, no. 47 (2015): 28200–28213.

[130] J. O. Jin, G. D. Lee, S. H. Nam, et al., “Sequential Ubiquitination of p53 by TRIM28, RLIM, and MDM2 in Lung Tumorigenesis,” Cell Death and Differentiation 28, no. 6 (2021): 1790–1803.

[131] P. Czerwińska, S. Mazurek, and M. Wiznerowicz, “The Complexity of TRIM28 Contribution to Cancer,” Journal of Biomedical Science 24, no. 1 (2017): 63.

[132] Z. Huang, X. Li, B. Tang, et al., “SETDB1 Modulates Degradation of Phosphorylated RB and Anticancer Efficacy of CDK4/6 Inhibitors,” Cancer Research 83, no. 6 (2023): 875–889.

[133] D. Deshmukh, J. Xu, X. Yang, H. Shimelis, S. Fang, and Y. Qiu, “Regulation of p27 (Kip1) by Ubiquitin E3 Ligase RNF6,” Pharmaceutics 14, no. 4 (2022): 802.

[134] X. Xu, T. Nakano, S. Wick, M. Dubay, and L. Brizuela, “Mechanism of Cdk2/Cyclin E Inhibition by p27 and p27 Phosphorylation,” Biochemistry 38, no. 27 (1999): 8713–8722.

[135] B. Mojsa, I. Lassot, and S. Desagher, “Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein,” Cells 3, no. 2 (2014): 418–437.

[136] Q. Zhong, W. Gao, F. Du, and X. Wang, “Mule/ARF-BP1, a BH3-only E3 Ubiquitin Ligase, Catalyzes the Polyubiquitination of Mcl-1 and Regulates Apoptosis,” Cell 121, no. 7 (2005): 1085–1095.

[137] H. Ren, J. Koo, B. Guan, et al., “The E3 Ubiquitin Ligases Beta-TrCP and FBXW7 Cooperatively Mediates GSK3-dependent Mcl-1 Degradation Induced by the Akt Inhibitor API-1, Resulting in Apoptosis,” Molecular cancer 12 (2013): 146.

[138] H. F. Yang-Yen, “Mcl-1: A Highly Regulated Cell Death and Survival Controller,” Journal of Biomedical Science 13, no. 2 (2006): 201–204.

[139] N. Edison, Y. Curtz, N. Paland, et al., “Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis,” Cell reports 21, no. 2 (2017): 442–454.

[140] C. Chen, T. S. Liu, S. C. Zhao, W. Z. Yang, Z. P. Chen, and Y. Yan, “XIAP Impairs Mitochondrial Function During Apoptosis by Regulating the Bcl-2 family in Renal Cell Carcinoma,” Exp Ther Med 15, no. 5 (2018): 4587–4593.

[141] B. A. Azakir, G. Desrochers, and A. Angers, “The Ubiquitin Ligase Itch Mediates the Antiapoptotic Activity of Epidermal Growth Factor by Promoting the Ubiquitylation and Degradation of the Truncated C-terminal Portion of Bid,” Febs Journal 277, no. 5 (2010): 1319–1330.

[142] B. N. Johnson, A. K. Berger, G. P. Cortese, and M. J. Lavoie, “The Ubiquitin E3 Ligase Parkin Regulates the Proapoptotic Function of Bax,” PNAS 109, no. 16 (2012): 6283–6288.

[143] A. Hantusch, K. K. Das, A. J. García-Sáez, T. Brunner, and M. Rehm, “Bax Retrotranslocation Potentiates Bcl-X's Antiapoptotic Activity and Is Essential for Switch-Like Transitions Between MOMP Competency and Resistance,” Cell Death & Disease 9, no. 4 (2018): 430.

[144] R. S. Whelan, K. Konstantinidis, A. C. Wei, et al., “Bax Regulates Primary Necrosis Through Mitochondrial Dynamics,” P Natl Acad Sci USA 109, no. 17 (2012): 6566–6571.

[145] L. Dubrez-Daloz, A. Dupoux, and J. Cartier, “IAPs—More Than Just Inhibitors of Apoptosis Proteins,” Cell Cycle 7, no. 8 (2008): 1036–1046.

[146] H. H. Cheung, S. Plenchette, C. J. Kern, D. J. Mahoney, and R. G. Korneluk, “The RING Domain of cIAP1 Mediates the Degradation of RING-bearing Inhibitor of Apoptosis Proteins by Distinct Pathways,” Molecular Biology of the Cell 19, no. 7 (2008): 2729–2740.

[147] Y. Nakatani, T. Kleffmann, K. Linke, S. M. Condon, M. G. Hinds, and C. L. Day, “Regulation of Ubiquitin Transfer by XIAP, a Dimeric RING E3 Ligase,” Biochemical Journal 450, no. 3 (2013): 629–638.

[148] Y. L. Yang and X. M. Li, “The IAP family: Endogenous Caspase Inhibitors With Multiple Biological Activities,” Cell Research 10, no. 3 (2000): 169–177.

[149] J. W. Blankenship, E. Varfolomeev, T. Goncharov, et al., “Ubiquitin Binding Modulates IAP Antagonist-stimulated Proteasomal Degradation of c-IAP1 and c-IAP2(1),” Biochemical Journal 417, no. 1 (2009): 149–160.

[150] E. M. Creagh, B. M. Murphy, P. J. Duriez, C. S. Duckett, and S. J. Martin, “Smac/Diablo Antagonizes Ubiquitin Ligase Activity of Inhibitor of Apoptosis Proteins,” Journal of Biological Chemistry 279, no. 26 (2004): 26906–26914.

[151] G. Wu, J. Chai, T. L. Suber, et al., “Structural Basis of IAP Recognition by Smac/DIABLO,” Nature 408, no. 6815 (2000): 1008–1012.

[152] R. Abbas and S. Larisch, “Targeting XIAP for Promoting Cancer Cell Death-The Story of ARTS and SMAC,” Cells 9, no. 3 (2020): 663.

[153] D. Mamriev, R. Abbas, F. M. Klingler, et al., “A Small-molecule ARTS Mimetic Promotes Apoptosis Through Degradation of both XIAP and Bcl-2,” Cell Death & Disease 11, no. 6 (2020).

[154] J. B. Garrison, R. G. Correa, M. Gerlic, et al., “ARTS and Siah Collaborate in a Pathway for XIAP Degradation,” Molecular Cell 41, no. 1 (2011): 107–116.

[155] B. Dumetier, A. Zadoroznyj, and L. Dubrez, “IAP-Mediated Protein Ubiquitination in Regulating Cell Signaling,” Cells 9, no. 5 (2020): 1118.

[156] Q. Hao, J. Chen, H. Lu, and X. Zhou, “The ARTS of p53-dependent Mitochondrial Apoptosis,” Journal of Molecular Cell Biology 14, no. 10 (2023): mjac074.

[157] D. Spano, C. Heck, P. De Antonellis, G. Christofori, and M. Zollo, “Molecular Networks That Regulate Cancer Metastasis,” Seminars in Cancer Biology 22, no. 3 (2012): 234–249.

[158] J. Davis Ryan, M. Welcker, and E. Clurman Bruce, “Tumor Suppression by the Fbw7 Ubiquitin Ligase: Mechanisms and Opportunities,” Cancer Cell 26, no. 4 (2014): 455–464.

[159] L. Y. Huang, J. Zhao, H. Chen, et al., “SCF(FBW7)-mediated Degradation of Brg1 Suppresses Gastric Cancer Metastasis,” Nature Communications 9, no. 1 (2018): 3569.

[160] N. R. Shin, E. H. Jeong, C. I. Choi, et al., “Overexpression of Snail Is Associated With Lymph Node Metastasis and Poor Prognosis in Patients With Gastric Cancer,” BMC cancer 12 (2012): 251.

[161] F. Xu, J. J. Li, M. D. Ni, et al., “FBW7 suppresses Ovarian Cancer Development by Targeting the N-methyladenosine Binding Protein YTHDF2,” Molecular cancer 20, no. 1 (2021): 45.

[162] S. J. Xia, L. Ji, L. Y. Tao, et al., “TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance,” Cell Mol Gastroenter 12, no. 3 (2021): 1121–1143.

[163] J. Xu, W. H. Zhou, F. Yang, et al., “The β-TrCP-FBXW2-SKP2 Axis Regulates Lung Cancer Cell Growth With FBXW2 Acting as a Tumour Suppressor,” Nature Communications 8 (2017): 14002.

[164] A. M. Pickrell and R. J. Youle, “The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson's Disease,” Neuron 85, no. 2 (2015): 257–273.

[165] L. Xu, D. C. Lin, D. Yin, and H. P. Koeffler, “An Emerging Role of PARK2 in Cancer,” Journal of Molecular Medicine 92, no. 1 (2014): 31–42.

[166] J. Liu, C. Zhang, H. Wu, et al., “Parkin Ubiquitinates Phosphoglycerate Dehydrogenase to Suppress Serine Synthesis and Tumor Progression,” Journal of Clinical Investigation 130, no. 6 (2020): 3253–3269.

[167] J. Liu, C. Zhang, Y. H. Zhao, et al., “Parkin Targets HIF-1α for Ubiquitination and Degradation to Inhibit Breast Tumor Progression,” Nature Communications 8, no. 1 (2017): 1823.

[168] A. Dasgupta, P. Mondal, S. Dalui, C. Das, and S. Roy, “Molecular Characterization of Substrate-induced Ubiquitin Transfer by UBR7-PHD Finger, a Newly Identified Histone H2BK120 Ubiquitin Ligase,” Febs Journal 289, no. 7 (2022): 1842–1857.

[169] S. Adhikary, D. Chakravarti, C. Terranova, et al., “Atypical Plant Homeodomain of UBR7 Functions as an H2BK120Ub Ligase and Breast Tumor Suppressor,” Nature Communications 10, no. 1 (2019): 1398.

[170] B. Der, H. Bugacov, B. M. Briantseva, and A. P. McMahon, “Cadherin Adhesion Complexes Direct Cell Aggregation in the Epithelial Transition of Wnt-induced Nephron Progenitor Cells,” Development (Cambridge, England) 151, no. 18 (2024): dev202303.

[171] M. T. Maher, A. S. Flozak, A. M. Stocker, A. Chenn, and C. J. Gottardi, “Activity of the β-catenin Phosphodestruction Complex at Cell-cell Contacts Is Enhanced by Cadherin-based Adhesion,” Journal of Cell Biology 186, no. 2 (2009): 219–228.

[172] J. Gu, W. Mao, W. Ren, et al., “Ubiquitin-protein Ligase E3C Maintains Non-small-cell Lung Cancer Stemness by Targeting AHNAK-p53 Complex,” Cancer Letters 443 (2019): 125–134.

[173] R. Aloni-Grinstein, Y. Shetzer, T. Kaufman, and V. Rotter, “p53: The Barrier to Cancer Stem Cell Formation,” Febs Letters 588, no. 16 (2014): 2580–2589.

[174] Y. Zhang, J. P. Xu, H. B. Fu, Z. R. Wei, D. J. Yang, and R. L. Yan, “UBE3C promotes Proliferation and Inhibits Apoptosis by Activating the β-catenin Signaling via Degradation of AXIN1 in Gastric Cancer,” Carcinogenesis 42, no. 2 (2021): 285–293.

[175] A. B. Jaffe and A. Hall, “Rho GTPases: Biochemistry and Biology,” Annu Rev Cell Dev Bi 21 (2005): 247–269.

[176] F. M. Vega and A. J. Ridley, “Rho GTPases in Cancer Cell Biology,” Febs Letters 582, no. 14 (2008): 2093–2101.

[177] D. C. Chen, Y. C. Li, X. W. Zhang, et al., “Ubiquitin Ligase TRIM65 Promotes Colorectal Cancer Metastasis by Targeting ARHGAP35 for Protein Degradation,” Oncogene 38, no. 37 (2019): 6429–6444.

[178] R. Sun, H. Y. Xie, J. X. Qian, et al., “FBXO22 Possesses both Protumorigenic and Antimetastatic Roles in Breast Cancer Progression,” Cancer Research 78, no. 18 (2018): 5274–5286.

[179] L. Zhang, J. Chen, D. Ning, et al., “FBXO22 promotes the Development of Hepatocellular Carcinoma by Regulating the Ubiquitination and Degradation of p21,” Journal of Experimental & Clinical Cancer Research 38, no. 1 (2019): 101.

[180] Y. Zheng, H. Chen, Y. Zhao, et al., “Knockdown of FBXO22 Inhibits Melanoma Cell Migration, Invasion and Angiogenesis via the HIF-1alpha/VEGF Pathway,” Investigational New Drugs 38, no. 1 (2020): 20–28.

[181] X. N. Zhu, P. He, L. Zhang, et al., “FBXO22 mediates Polyubiquitination and Inactivation of LKB1 to Promote Lung Cancer Cell Growth,” Cell death & disease 10, no. 7 (2019): 486.

[182] K. M. Hargadon, C. E. Johnson, and C. J. Williams, “Immune Checkpoint Blockade Therapy for Cancer: An Overview of FDA-approved Immune Checkpoint Inhibitors,” International Immunopharmacology 62 (2018): 29–39.

[183] H. Shi, J. Lan, and J. Yang, “Mechanisms of Resistance to Checkpoint Blockade Therapy,” Advances in Experimental Medicine and Biology 1248 (2020): 83–117.

[184] Y. Nakamura, “Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events,” Front Med (Lausanne) 6 (2019): 119.

[185] C. Lyle, S. Richards, K. Yasuda, et al., “c-Cbl Targets PD-1 in Immune Cells for Proteasomal Degradation and Modulates Colorectal Tumor Growth,” Scientific Reports 9, no. 1 (2019): 20257.

[186] S. Wang, L. Xu, and X. Che, “E3 ubiquitin Ligases Cbl-b and c-Cbl Downregulate PD-L1 in EGFR Wild-type Non-small Cell Lung Cancer,” Febs Letters 592, no. 4 (2018): 621–630.

[187] H. Yao and J. Xu, “Regulation of Cancer Immune Checkpoint: Mono- and Poly-Ubiquitination: Tags for Fate,” Advances in Experimental Medicine and Biology 1248 (2020): 295–324.

[188] Y. Jiang, M. Chen, H. Nie, and Y. Yuan, “PD-1 and PD-L1 in Cancer Immunotherapy: Clinical Implications and Future Considerations,” Human vaccines & immunotherapeutics 15, no. 5 (2019): 1111–1122.

[189] T. M. Serman and M. U. Gack, “FBXO38 Drives PD-1 to Destruction,” Trends in Immunology 40, no. 2 (2019): 81–83.

[190] X. Meng, X. Liu, X. Guo, et al., “FBXO38 mediates PD-1 Ubiquitination and Regulates Anti-tumour Immunity of T Cells,” Nature 564, no. 7734 (2018): 130–135.

[191] H. Tang, Y. Liang, R. A. Anders, et al., “PD-L1 on Host Cells Is Essential for PD-L1 Blockade-mediated Tumor Regression,” Journal of Clinical Investigation 128, no. 2 (2018): 580–588.

[192] C. W. Li, S. O. Lim, W. Xia, et al., “Glycosylation and Stabilization of Programmed Death Ligand-1 Suppresses T-cell Activity,” Nature Communications 7 (2016): 12632.

[193] J. Zhang, X. Bu, H. Wang, et al., “Cyclin D-CDK4 Kinase Destabilizes PD-L1 via Cullin 3-SPOP to Control Cancer Immune Surveillance,” Nature 553, no. 7686 (2018): 91–95.

[194] A. Hosseini, T. Gharibi, F. Marofi, Z. Babaloo, and B. Baradaran, “CTLA-4: From Mechanism to Autoimmune Therapy,” International Immunopharmacology 80 (2020): 106221.

[195] B. Rowshanravan, N. Halliday, and D. M. Sansom, “CTLA-4: A Moving Target in Immunotherapy,” Blood 131, no. 1 (2018): 58–67.

[196] L. Coscoy, D. J. Sanchez, and D. Ganem, “A Novel Class of Herpesvirus-encoded Membrane-bound E3 Ubiquitin Ligases Regulates Endocytosis of Proteins Involved in Immune Recognition,” Journal of Cell Biology 155, no. 7 (2001): 1265–1273.

[197] E. Alix, C. Godlee, O. Cerny, et al., “The Tumour Suppressor TMEM127 Is a Nedd4-Family E3 Ligase Adaptor Required by Salmonella SteD to Ubiquitinate and Degrade MHC Class II Molecules,” Cell Host & Microbe 28, no. 1 (2020): 54–68.e7.

[198] D. J. van den Boomen and P. J. Lehner, “Identifying the ERAD Ubiquitin E3 Ligases for Viral and Cellular Targeting of MHC Class I,” Molecular Immunology 68, no. 2 (2015): 106–111. Pt A.

[199] T. Hu, H. Liu, Z. Liang, et al., “Tumor-intrinsic CD47 Signal Regulates Glycolysis and Promotes Colorectal Cancer Cell Growth and Metastasis,” Theranostics 10, no. 9 (2020): 4056–4072.

[200] I. E. Wertz, “TNFR1-activated NF-kappaB Signal Transduction: Regulation by the Ubiquitin/Proteasome System,” Current Opinion in Chemical Biology 23 (2014): 71–77.

[201] L. Elton, I. Carpentier, K. Verhelst, J. Staal, and R. Beyaert, “The Multifaceted Role of the E3 Ubiquitin Ligase HOIL-1: Beyond Linear Ubiquitination,” Immunological Reviews 266, no. 1 (2015): 208–221.

[202] G. Cildir, K. C. Low, and V. Tergaonkar, “Noncanonical NF-kappaB Signaling in Health and Disease,” Trends in Molecular Medicine 22, no. 5 (2016): 414–429.

[203] S. C. Sun, “The Non-canonical NF-kappaB Pathway in Immunity and Inflammation,” Nature Reviews Immunology 17, no. 9 (2017): 545–558.

[204] S. C. Sun, “The Noncanonical NF-κB Pathway,” Immunological Reviews 246, no. 1 (2012): 125–140.

[205] M. Kortylewski and H. Yu, “Role of Stat3 in Suppressing Anti-tumor Immunity,” Current Opinion in Immunology 20, no. 2 (2008): 228–233.

[206] D. Gotthardt, J. Trifinopoulos, V. Sexl, and E. M. Putz, “JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation,” Frontiers in immunology 10 (2019): 2590.

[207] L. Shen, K. Evel-Kabler, R. Strube, and S. Y. Chen, “Silencing of SOCS1 Enhances Antigen Presentation by Dendritic Cells and Antigen-specific Anti-tumor Immunity,” Nature Biotechnology 22, no. 12 (2004): 1546–1553.

[208] K. Rakesh and D. K. Agrawal, “Controlling Cytokine Signaling by Constitutive Inhibitors,” Biochemical Pharmacology 70, no. 5 (2005): 649–657.

[209] M. Heusinkveld and S. H. van der Burg, “Identification and Manipulation of Tumor Associated Macrophages in human Cancers,” Journal of translational medicine 9 (2011): 216.

[210] M. H. Barros, F. Hauck, J. H. Dreyer, B. Kempkes, and G. Niedobitek, “Macrophage Polarisation: An Immunohistochemical Approach for Identifying M1 and M2 Macrophages,” PLoS ONE 8, no. 11 (2013): e80908.

[211] K. Meissl, S. Macho-Maschler, M. Muller, and B. Strobl, “The Good and the Bad Faces of STAT1 in Solid Tumours,” Cytokine 89 (2017): 12–20.

[212] C. Yuan, J. Qi, X. Zhao, and C. Gao, “Smurf1 protein Negatively Regulates Interferon-γ Signaling Through Promoting STAT1 protein Ubiquitination and Degradation,” Journal of Biological Chemistry 287, no. 21 (2012): 17006–17015.

[213] D. W. Lawrence and J. Kornbluth, “E3 ubiquitin Ligase NKLAM Ubiquitinates STAT1 and Positively Regulates STAT1-mediated Transcriptional Activity,” Cell Signalling 28, no. 12 (2016): 1833–1841.

[214] M. Jiang, P. Chen, L. Wang, et al., “cGAS-STING, an Important Pathway in Cancer Immunotherapy,” Journal of hematology & oncology 13, no. 1 (2020): 81.

[215] T. Tsuchida, J. Zou, T. Saitoh, et al., “The Ubiquitin Ligase TRIM56 Regulates Innate Immune Responses to Intracellular Double-stranded DNA,” Immunity 33, no. 5 (2010): 765–776.

[216] J. Zhang, M. M. Hu, Y. Y. Wang, and H. B. Shu, “TRIM32 protein Modulates Type I Interferon Induction and Cellular Antiviral Response by Targeting MITA/STING protein for K63-linked Ubiquitination,” Journal of Biological Chemistry 287, no. 34 (2012): 28646–28655.

[217] B. Zhong, L. Zhang, C. Lei, et al., “The Ubiquitin Ligase RNF5 Regulates Antiviral Responses by Mediating Degradation of the Adaptor Protein MITA,” Immunity 30, no. 3 (2009): 397–407.

[218] Y. Qin, M. T. Zhou, M. M. Hu, et al., “RNF26 temporally Regulates Virus-triggered Type I Interferon Induction by Two Distinct Mechanisms,” Plos Pathogens 10, no. 9 (2014): e1004358.

[219] J. Xing, A. Zhang, H. Zhang, et al., “TRIM29 promotes DNA Virus Infections by Inhibiting Innate Immune Response,” Nature Communications 8, no. 1 (2017): 945.

[220] Q. Li, L. Lin, Y. Tong, et al., “TRIM29 negatively Controls Antiviral Immune Response Through Targeting STING for Degradation,” Cell Discovery 4 (2018): 13.

[221] Y. Wang, Q. Lian, B. Yang, et al., “TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING,” Plos Pathogens 11, no. 6 (2015): e1005012.

[222] M. K. Gupta and R. Y. Qin, “Mechanism and Its Regulation of Tumor-induced Angiogenesis,” World Journal of Gastroenterology 9, no. 6 (2003): 1144–1155.

[223] R. Li, J. Shao, Y. J. Jin, et al., “Endothelial FAT1 Inhibits Angiogenesis by Controlling YAP/TAZ Protein Degradation via E3 Ligase MIB2,” Nature Communications 14, no. 1 (2023): 1980.

[224] Y. Guo, Y. Wang, H. Liu, X. Jiang, and S. Lei, “High Glucose Environment Induces NEDD4 Deficiency That Impairs Angiogenesis and Diabetic Wound Healing,” Journal of Dermatological Science 112, no. 3 (2023): 148–157.

[225] M. Ma, W. Yang, Z. Cai, et al., “SMAD-specific E3 Ubiquitin Ligase 2 Promotes Angiogenesis by Facilitating PTX3 Degradation in MSCs From Patients With Ankylosing Spondylitis,” Stem Cells 39, no. 5 (2021): 581–599.

[226] H. Ohnuki, H. Inoue, N. Takemori, et al., “BAZF, a Novel Component of cullin3-based E3 Ligase Complex, Mediates VEGFR and Notch Cross-signaling in Angiogenesis,” Blood 119, no. 11 (2012): 2688–2698.

[227] J. Li, Y. Xu, X. D. Long, et al., “Cbx4 governs HIF-1alpha to Potentiate Angiogenesis of Hepatocellular Carcinoma by Its SUMO E3 Ligase Activity,” Cancer Cell 25, no. 1 (2014): 118–131.

[228] Y. Zhang, H. Qian, B. Wu, et al., “E3 Ubiquitin Ligase NEDD4 family‑Regulatory Network in Cardiovascular Disease,” Int J Biol Sci 16, no. 14 (2020): 2727–2740.

[229] X. Chen, J. Ma, Z. W. Wang, and Z. Wang, “The E3 Ubiquitin Ligases Regulate Inflammation in Cardiovascular Diseases,” Seminars in cell & developmental biology 154, no. Pt C (2024): 167–174.

[230] M. S. Willis, A. Bevilacqua, T. Pulinilkunnil, P. Kienesberger, M. Tannu, and C. Patterson, “The Role of Ubiquitin Ligases in Cardiac Disease,” Journal of Molecular and Cellular Cardiology 71 (2014): 43–53.

[231] A. Piek, R. A. de Boer, and H. H. Silljé, “The Fibrosis-cell Death Axis in Heart Failure,” Heart Failure Reviews 21, no. 2 (2016): 199–211.

[232] R. Gogiraju, M. L. Bochenek, and K. Schäfer, “Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure,” Frontiers in Cardiovascular Medicine 6 (2019): 20.

[233] G. Savarese and L. H. Lund, “Global Public Health Burden of Heart Failure,” Card Fail Rev 3, no. 1 (2017): 7–11.

[234] Z. Wang, S. Sun, L. Huang, et al., “Pathological Roles of Ubiquitination and Deubiquitination Systems in Sepsis-induced Myocardial Dysfunction,” Biomol Biomed 25, no. 7 (2025): 1444–1458.

[235] K. Dadson, L. Hauck, Z. Hao, et al., “The E3 Ligase Mule Protects the Heart Against Oxidative Stress and Mitochondrial Dysfunction Through Myc-dependent Inactivation of Pgc-1alpha and Pink1,” Scientific Reports 7 (2017): 41490.

[236] A. Borlepawar, N. Frey, and A. Y. Rangrez, “A Systematic View on E3 Ligase Ring TRIMmers With a Focus on Cardiac Function and Disease,” Trends in Cardiovascular Medicine 29, no. 1 (2019): 1–8.

[237] X. Hu, J. Yu, Z. Lin, R. Feng, Z. W. Wang, and G. Chen, “The Emerging Role of WWP1 in Cancer Development and Progression,” Cell Death Discov 7, no. 1 (2021): 163.

[238] F. Bernassola, G. Chillemi, and G. Melino, “HECT-Type E3 Ubiquitin Ligases in Cancer,” Trends in Biochemical Sciences 44, no. 12 (2019): 1057–1075.

[239] D. Zhao, G. Zhong, J. Li, et al., “Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination,” Circulation 144, no. 9 (2021): 694–711.

[240] W. A. Basheer, B. S. Harris, H. L. Mentrup, et al., “Cardiomyocyte-specific Overexpression of the Ubiquitin Ligase Wwp1 Contributes to Reduction in Connexin 43 and Arrhythmogenesis,” Journal of Molecular and Cellular Cardiology 88 (2015): 1–13.

[241] A. Behera and A. B. M. Reddy, “WWP1 E3 ligase at the Crossroads of Health and Disease,” Cell death & disease 14, no. 12 (2023): 853.

[242] H. Jiang, C. Y. Chiang, Z. Chen, et al., “Enzymatic Analysis of WWP2 E3 Ubiquitin Ligase Using Protein Microarrays Identifies Autophagy-related Substrates,” Journal of Biological Chemistry 298, no. 5 (2022): 101854.

[243] H. Chen, G. Chew, N. Devapragash, et al., “The E3 Ubiquitin Ligase WWP2 Regulates Pro-fibrogenic Monocyte Infiltration and Activity in Heart Fibrosis,” Nature Communications 13, no. 1 (2022): 7375.

[244] H. Chen, A. Moreno-Moral, F. Pesce, et al., “WWP2 regulates Pathological Cardiac Fibrosis by Modulating SMAD2 Signaling,” Nature Communications 10, no. 1 (2019): 3616.

[245] Z. Li, B. Wu, J. Chen, et al., “WWP2 protects Against Sepsis-induced Cardiac Injury Through Inhibiting Cardiomyocyte Ferroptosis,” J Transl Int Med 12, no. 1 (2024): 35–50.

[246] M. Shi, F. Su, Z. Dong, et al., “TRIM16 exerts Protective Function on Myocardial Ischemia/Reperfusion Injury Through Reducing Pyroptosis and Inflammation via NLRP3 Signaling,” Biochemical and Biophysical Research Communications 632 (2022): 122–128.

[247] J. Liu, W. Li, K. Q. Deng, et al., “The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy,” Circulation Research 130, no. 10 (2022): 1586–1600.

[248] X. Guo, M. Liu, B. Han, et al., “Upregulation of TRIM16 Mitigates Doxorubicin-induced Cardiotoxicity by Modulating TAK1 and YAP/Nrf2 Pathways in Mice,” Biochemical Pharmacology 220 (2024): 116009.

[249] C. Chen, X. Hu, and X. Chen, “Saikosaponin A Protects Against Uremic Toxin Indole‑3 Acetic Acid‑Induced Damage to the Myocardium,” Mol Med Rep 28, no. 3 (2023): 159.

[250] J. Goto, Y. Otaki, T. Watanabe, and M. Watanabe, “The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease,” International Journal of Molecular Sciences 22, no. 11 (2021): 6065.

[251] J. Goto, Y. Otaki, T. Watanabe, et al., “HECT (Homologous to the E6-AP Carboxyl Terminus)-Type Ubiquitin E3 Ligase ITCH Attenuates Cardiac Hypertrophy by Suppressing the Wnt/Beta-Catenin Signaling Pathway,” Hypertension 76, no. 6 (2020): 1868–1878.

[252] Y. Otaki, H. Takahashi, T. Watanabe, et al., “HECT-Type Ubiquitin E3 Ligase ITCH Interacts with Thioredoxin-Interacting Protein and Ameliorates Reactive Oxygen Species-Induced Cardiotoxicity,” Journal of the American Heart Association 5, no. 1 (2016): e002485.

[253] X. Li, X. Hu, Q. Chen, and T. Jiang, “Bone Marrow Mesenchymal Stem Cell-derived Exosomes Carrying E3 Ubiquitin Ligase ITCH Attenuated Cardiomyocyte Apoptosis by Mediating Apoptosis Signal-regulated Kinase-1,” Pharmacogenet Genomics 33, no. 6 (2023): 117–125.

[254] J. Francisco and D. P. Del Re, “Inflammation in Myocardial Ischemia/Reperfusion Injury: Underlying Mechanisms and Therapeutic Potential,” Antioxidants (Basel) 12, no. 11 (2023): 1944.

[255] M. Algoet, S. Janssens, U. Himmelreich, et al., “Myocardial Ischemia-reperfusion Injury and the Influence of Inflammation,” Trends in Cardiovascular Medicine 33, no. 6 (2023): 357–366.

[256] Y. Liu, L. Li, Z. Wang, J. Zhang, and Z. Zhou, “Myocardial Ischemia-reperfusion Injury; Molecular Mechanisms and Prevention,” Microvascular Research 149 (2023): 104565.

[257] A. Eiyama and K. Okamoto, “PINK1/Parkin-mediated Mitophagy in Mammalian Cells,” Current Opinion in Cell Biology 33 (2015): 95–101.

[258] T. Sun, W. Ding, T. Xu, et al., “Parkin Regulates Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury by Targeting Cyclophilin-D,” Antioxid Redox Signaling 31, no. 16 (2019): 1177–1193.

[259] L. Ai, J. de Freitas Germano, C. Huang, et al., “Enhanced Parkin-mediated Mitophagy Mitigates Adverse Left Ventricular Remodelling After Myocardial Infarction: Role of PR-364,” European Heart Journal 46, no. 4 (2025): 380–393.

[260] M. Abudureyimu, W. Yu, R. Y. Cao, Y. Zhang, H. Liu, and H. Zheng, “Berberine Promotes Cardiac Function by Upregulating PINK1/Parkin-Mediated Mitophagy in Heart Failure,” Front Physiol 11 (2020): 565751.

[261] Y. Li, C. Zuo, X. Wu, et al., “FBXL8 inhibits Post-myocardial Infarction Cardiac Fibrosis by Targeting Snail1 for Ubiquitin-proteasome Degradation,” Cell death & disease 15, no. 4 (2024): 263.

[262] B. Mason and H. Laman, “The FBXL family of F-box Proteins: Variations on a Theme,” Open Biol 10, no. 11 (2020): 200319.

[263] S. Liu, Y. Bi, T. Han, et al., “The E3 Ubiquitin Ligase MARCH2 Protects Against Myocardial Ischemia-reperfusion Injury Through Inhibiting Pyroptosis via Negative Regulation of PGAM5/MAVS/NLRP3 Axis,” Cell Discovery 10, no. 1 (2024): 24.

[264] L. Fang, Y. Tao, G. Che, Y. Yun, M. Ren, and Y. Liu, “WSB1, as an E3 Ligase, Restrains Myocardial Ischemia-reperfusion Injury by Activating β-catenin Signaling via Promoting GSK3β Ubiquitination,” Molecular Medicine 30, no. 1 (2024): 31.

[265] Y. Zhang, Y. Zeng, M. Wang, et al., “Cardiac-specific Overexpression of E3 Ligase Nrdp1 Increases Ischemia and Reperfusion-induced Cardiac Injury,” Basic Research in Cardiology 106, no. 3 (2011): 371–383.

[266] K. Malekmohammad, E. E. Bezsonov, and M. Rafieian-Kopaei, “Role of Lipid Accumulation and Inflammation in Atherosclerosis: Focus on Molecular and Cellular Mechanisms,” Frontiers in Cardiovascular Medicine 8 (2021): 707529.

[267] Y. Liu, X. Zhang, L. Yu, et al., “E3 ubiquitin Ligase RNF128 Promotes Lys63-linked Polyubiquitination on SRB1 in Macrophages and Aggravates Atherosclerosis,” Nature Communications 16, no. 1 (2025): 2185.

[268] J. Holloway, A. Seeley, N. Cobbe, R. C. Turkington, D. B. Longley, and E. Evergren, “The E3 Ubiquitin Ligase Itch Regulates Death Receptor and Cholesterol Trafficking to Affect TRAIL-mediated Apoptosis,” Cell death & disease 15, no. 1 (2024): 40.

[269] Y. Zeng, S. Fu, Y. Xia, G. Meng, and X. Xu, “Itchy E3 Ubiquitin Ligase-Mediated Ubiquitination of Ferritin Light Chain Contributes to Endothelial Ferroptosis in Atherosclerosis,” International Journal of Molecular Sciences 25, no. 24 (2024): 13524.

[270] M. Yamamoto, J. Gohda, T. Akiyama, and J. I. Inoue, “TNF Receptor-associated Factor 6 (TRAF6) Plays Crucial Roles in Multiple Biological Systems Through Polyubiquitination-mediated NF-kappaB Activation,” Proc Jpn Acad Ser B Phys Biol Sci 97, no. 4 (2021): 145–160.

[271] J. Yang, X. Zhou, J. Lu, and M. Li, “miR-146-5p Restrains Calcification of Vascular Smooth Muscle Cells by Suppressing TRAF6,” Open Med (Wars) 17, no. 1 (2022): 1515–1527.

[272] L. H. Dong, L. Li, Y. Song, et al., “TRAF6-Mediated SM22alpha K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival in Vitro and in Vivo,” Circulation Research 117, no. 8 (2015): 684–694.

[273] P. Kong, Z. Y. Cui, X. F. Huang, D. D. Zhang, R. J. Guo, and M. Han, “Inflammation and Atherosclerosis: Signaling Pathways and Therapeutic Intervention,” Signal Transduct Target Ther 7, no. 1 (2022): 131.

[274] M. Lei, S. C. Salvage, A. P. Jackson, and C. L. Huang, “Cardiac Arrhythmogenesis: Roles of Ion Channels and Their Functional Modification,” Front Physiol 15 (2024): 1342761.

[275] C. E. Blandin, B. J. Gravez, S. N. Hatem, and E. Balse, “Remodeling of Ion Channel Trafficking and Cardiac Arrhythmias,” Cells 10, no. 9 (2021): 2417.

[276] K. F. Harvey, A. Dinudom, P. Komwatana, et al., “All Three WW Domains of Murine Nedd4 Are Involved in the Regulation of Epithelial Sodium Channels by Intracellular Na+,” Journal of Biological Chemistry 274, no. 18 (1999): 12525–12530.

[277] D. Rotin, O. Staub, and R. Haguenauer-Tsapis, “Ubiquitination and Endocytosis of Plasma Membrane Proteins: Role of Nedd4/Rsp5p family of Ubiquitin-protein Ligases,” Journal of Membrane Biology 176, no. 1 (2000): 1–17.

[278] T. Fukushima, H. Yoshihara, H. Furuta, et al., “Nedd4-induced Monoubiquitination of IRS-2 Enhances IGF Signalling and Mitogenic Activity,” Nature Communications 6 (2015): 6780.

[279] K. M. Wright, S. Nathan, H. Jiang, et al., “NEDD4L intramolecular Interactions Regulate Its Auto and Substrate Na(V)1.5 Ubiquitination,” Journal of Biological Chemistry 300, no. 3 (2024): 105715.

[280] X. Liu, J. Ge, C. Chen, et al., “FAT10 protects Against Ischemia-induced Ventricular Arrhythmia by Decreasing Nedd4-2/Nav1.5 Complex Formation,” Cell death & disease 12, no. 1 (2021): 25.

[281] Q. Nie, J. Zhao, H. Zhang, D. Zhang, and W. Xie, “WWP2 and PPP1R3A Are Abnormally Regulated in Arrhythmia-induced Cardiac Damage,” 3 Biotech 11, no. 4 (2021): 185.

[282] T. Ciarambino, G. Menna, G. Sansone, and M. Giordano, “Cardiomyopathies: An Overview,” International Journal of Molecular Sciences 22, no. 14 (2021): 7722.

[283] W. J. McKenna, B. J. Maron, and G. Thiene, “Classification, Epidemiology, and Global Burden of Cardiomyopathies,” Circulation Research 121, no. 7 (2017): 722–730.

[284] D. P. Narendra and R. J. Youle, “The Role of PINK1-Parkin in Mitochondrial Quality Control,” Nature Cell Biology 26, no. 10 (2024): 1639–1651.

[285] D. Shao, S. C. Kolwicz, and P. Wang, “Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy through Regulating Parkin-Mediated Mitophagy,” Circulation 142, no. 10 (2020): 983–997.

[286] C. Yang, C. Xiao, Z. Ding, X. Zhai, J. Liu, and M. Yu, “Canagliflozin Mitigates Diabetic Cardiomyopathy Through Enhanced PINK1-Parkin Mitophagy,” International Journal of Molecular Sciences 25, no. 13 (2024): 7008.

[287] Z. Chen, S. Li, M. Liu, et al., “Nicorandil Alleviates Cardiac Microvascular Ferroptosis in Diabetic Cardiomyopathy: Role of the Mitochondria-localized AMPK-Parkin-ACSL4 Signaling Pathway,” Pharmacological Research 200 (2024): 107057.

[288] H. Xu, W. Yu, M. Sun, et al., “Syntaxin17 contributes to Obesity Cardiomyopathy Through Promoting Mitochondrial Ca(2+) Overload in a Parkin-MCUb-dependent Manner,” Metabolism 143 (2023): 155551.

[289] Y. F. Wang, Z. Y. An, J. W. Li, Z. K. Dong, and W. L. Jin, “MG53/TRIM72: Multi-organ Repair Protein and Beyond,” Front Physiol 15 (2024): 1377025.

[290] Z. Li, L. Wang, H. Yue, et al., “MG53, A Tissue Repair Protein With Broad Applications in Regenerative Medicine,” Cells 10, no. 1 (2021): 122.

[291] J. Liu, H. Zhu, Y. Zheng, et al., “Cardioprotection of Recombinant human MG53 Protein in a Porcine Model of Ischemia and Reperfusion Injury,” Journal of Molecular and Cellular Cardiology 80 (2015): 10–19.

[292] J. Guo, F. Jia, Y. Jiang, et al., “Potential Role of MG53 in the Regulation of Transforming-growth-factor-beta1-induced Atrial Fibrosis and Vulnerability to Atrial Fibrillation,” Experimental Cell Research 362, no. 2 (2018): 436–443.

[293] X. Han, D. Chen, N. Liufu, et al., “MG53 Protects Against Sepsis-Induced Myocardial Dysfunction by Upregulating Peroxisome Proliferator-Activated Receptor-alpha,” Oxid Med Cell Longev 2020 (2020): 7413693.

[294] J. Li, R. Jiang, Y. Hou, and A. Lin, “Mesenchymal Stem Cells-derived Exosomes Prevent Sepsis-induced Myocardial Injury by a CircRTN4/miR-497-5p/MG53 Pathway,” Biochemical and Biophysical Research Communications 618 (2022): 133–140.

[295] W. Liu, G. Wang, C. Zhang, et al., “MG53, A Novel Regulator of KChIP2 and I(to,f), Plays a Critical Role in Electrophysiological Remodeling in Cardiac Hypertrophy,” Circulation 139, no. 18 (2019): 2142–2156.

[296] R. Song, W. Peng, Y. Zhang, et al., “Central Role of E3 Ubiquitin Ligase MG53 in Insulin Resistance and Metabolic Disorders,” Nature 494, no. 7437 (2013): 375–379.

[297] H. K. Wu, Y. Zhang, C. M. Cao, et al., “Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin Response and Metabolic Homeostasis,” Circulation 139, no. 7 (2019): 901–914.

[298] H. Feng, H. Shen, M. J. Robeson, et al., “MG53 E3 Ligase-Dead Mutant Protects Diabetic Hearts from Acute Ischemic/Reperfusion Injury and Ameliorates Diet-Induced Cardiometabolic Damage,” Diabetes 71, no. 2 (2022): 298–314.

[299] B. Reilly-O'Donnell, E. Ferraro, and R. Tikhomirov, “Protective Effect of UDCA Against IL-11- induced Cardiac Fibrosis Is Mediated by TGR5 Signalling,” Frontiers in Cardiovascular Medicine 11 (2024): 1430772.

[300] A. Doria, M. Zen, S. Bettio, et al., “Autoinflammation and Autoimmunity: Bridging the Divide,” Autoimmunity Reviews 12, no. 1 (2012): 22–30.

[301] F. Shirafkan, L. Hensel, and K. Rattay, “Immune Tolerance and the Prevention of Autoimmune Diseases Essentially Depend on Thymic Tissue Homeostasis,” Frontiers in immunology 15 (2024): 1339714.

[302] L. Han, T. Wu, Q. Zhang, A. Qi, and X. Zhou, “Immune Tolerance Regulation Is Critical to Immune Homeostasis,” Journal of Immunology Research 2025 (2025): 5006201.

[303] S. A. Bhat, Z. Vasi, R. Adhikari, et al., “Ubiquitin Proteasome System in Immune Regulation and Therapeutics,” Current Opinion in Pharmacology 67 (2022): 102310.

[304] S. Shao, D. Zhou, J. Feng, et al., “Regulation of Inflammation and Immunity in Sepsis by E3 Ligases,” Front Endocrinol (Lausanne) 14 (2023): 1124334.

[305] M. A. Ameer, H. Chaudhry, J. Mushtaq, et al., “An Overview of Systemic Lupus Erythematosus (SLE) Pathogenesis, Classification, and Management,” Cureus 14, no. 10 (2022): e30330.

[306] A. Fava and M. Petri, “Systemic Lupus Erythematosus: Diagnosis and Clinical Management,” Journal of Autoimmunity 96 (2019): 1–13.

[307] M. Kiriakidou and C. L. Ching, “Systemic Lupus Erythematosus,” Annals of Internal Medicine 172, no. 11 (2020): Itc81–itc96.

[308] D. S. Pisetsky and P. E. Lipsky, “New Insights Into the Role of Antinuclear Antibodies in Systemic Lupus Erythematosus,” Nat Rev Rheumatol 16, no. 10 (2020): 565–579.

[309] M. K. Crow, “Pathogenesis of Systemic Lupus Erythematosus: Risks, Mechanisms and Therapeutic Targets,” Annals of the Rheumatic Diseases 82, no. 8 (2023): 999–1014.

[310] L. Ronnblom and D. Leonard, “Interferon Pathway in SLE: One Key to Unlocking the Mystery of the Disease,” Lupus Sci Med 6, no. 1 (2019): e000270.

[311] H. Sutanto and Y. Yuliasih, “Disentangling the Pathogenesis of Systemic Lupus Erythematosus: Close Ties Between Immunological, Genetic and Environmental Factors,” Medicina (Kaunas, Lithuania) 59, no. 6 (2023): 1033.

[312] Y. Kunishita, R. Yoshimi, R. Kamiyama, et al., “Anti-TRIM21 Antibody Is Associated With Aberrant B-cell Function and Type I Interferon Production in Systemic Lupus erythematosus,” Lupus 30, no. 13 (2021): 2054–2065.

[313] C. Li, A. Ma, Y. Bai, et al., “TRIM21 promotes Type I Interferon by Inhibiting the Autophagic Degradation of STING via p62/SQSTM1 Ubiquitination in Systemic Lupus Erythematosus,” Acta Biochim Biophys Sin (Shanghai) 57, no. 5 (2025): 834–846.

[314] C. H. Hsu and Y. L. Yu, “The Interconnected Roles of TRIM21/Ro52 in Systemic Lupus Erythematosus, Primary Sjogren's Syndrome, Cancers, and Cancer Metabolism,” Cancer cell international 23, no. 1 (2023): 289.

[315] K. Bachmaier, C. Krawczyk, I. Kozieradzki, et al., “Negative Regulation of Lymphocyte Activation and Autoimmunity by the Molecular Adaptor Cbl-b,” Nature 403, no. 6766 (2000): 211–216.

[316] J. Romo-Tena, S. Rajme-Lopez, L. Aparicio-Vera, J. Alcocer-Varela, and D. Gomez-Martin, “Lys63-polyubiquitination by the E3 Ligase casitas B-lineage Lymphoma-b (Cbl-b) Modulates Peripheral Regulatory T Cell Tolerance in Patients With Systemic Lupus Erythematosus,” Clinical and Experimental Immunology 191, no. 1 (2018): 42–49.

[317] L. Doniz-Padilla, V. Martinez-Jimenez, P. Nino-Moreno, et al., “Expression and Function of Cbl-b in T Cells From Patients With Systemic Lupus Erythematosus, and Detection of the 2126 A/G Cblb Gene Polymorphism in the Mexican Mestizo Population,” Lupus 20, no. 6 (2011): 628–635.

[318] Y. Kitaura, I. K. Jang, Y. Wang, et al., “Control of the B Cell-intrinsic Tolerance Programs by Ubiquitin Ligases Cbl and Cbl-b,” Immunity 26, no. 5 (2007): 567–578.

[319] A. Martens and G. van Loo, “A20 at the Crossroads of Cell Death, Inflammation, and Autoimmunity,” Cold Spring Harbor perspectives in biology 12, no. 1 (2020): a036418.

[320] L. Vereecke, R. Beyaert, and G. van Loo, “The Ubiquitin-editing Enzyme A20 (TNFAIP3) Is a central Regulator of Immunopathology,” Trends in Immunology 30, no. 8 (2009): 383–391.

[321] D. Li, L. Wang, Y. Fan, et al., “Down-regulation of A20 mRNA Expression in Peripheral Blood Mononuclear Cells From Patients With Systemic Lupus Erythematosus,” Journal of Clinical Immunology 32, no. 6 (2012): 1287–1291.

[322] I. Adrianto, F. Wen, A. Templeton, et al., “Association of a Functional Variant Downstream of TNFAIP3 With Systemic Lupus Erythematosus,” Nature Genetics 43, no. 3 (2011): 253–258.

[323] S. Wang, F. Wen, G. B. Wiley, M. T. Kinter, and P. M. Gaffney, “An Enhancer Element Harboring Variants Associated With Systemic Lupus Erythematosus Engages the TNFAIP3 Promoter to Influence A20 Expression,” PLos Genet 9, no. 9 (2013): e1003750.

[324] S. Pasula, J. Gopalakrishnan, Y. Fu, et al., “Systemic Lupus Erythematosus Variants Modulate the Function of an Enhancer Upstream of TNFAIP3,” Frontiers in Genetics 13 (2022): 1011965.

[325] J. Fan, S. Iwata, Y. Tanaka, et al., “Kdm5a promotes B Cell Activation in Systemic Lupus Erythematosus via Downregulation of A20 by Histone Modification,” Pathology, Research and Practice (2021): 153653.

[326] R. Duan, Q. Liu, J. Li, et al., “A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus,” Journal of Clinical Immunology 39, no. 8 (2019): 795–804.

[327] L. Odqvist, Z. Jevnikar, R. Riise, et al., “Genetic Variations in A20 DUB Domain Provide a Genetic Link to Citrullination and Neutrophil Extracellular Traps in Systemic Lupus Erythematosus,” Annals of the Rheumatic Diseases 78, no. 10 (2019): 1363–1370.

[328] L. Sun, L. X. Zou, Y. C. Han, et al., “A20 overexpression Exerts Protective Effects on Podocyte Injury in Lupus Nephritis by Downregulating UCH-L1,” Journal of Cellular Physiology 234, no. 9 (2019): 16191–16204.

[329] M. Li, X. Shi, F. Chen, and F. Hao, “Daphnetin Inhibits Inflammation in the NZB/W F1 Systemic Lupus Erythematosus Murine Model via Inhibition of NF-kappaB Activity,” Exp Ther Med 13, no. 2 (2017): 455–460.

[330] J. S. Smolen, D. Aletaha, A. Barton, et al., “Rheumatoid Arthritis,” Nature reviews Disease primers 4 (2018): 18001.

[331] Y. J. Lin, M. Anzaghe, and S. Schulke, “Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis,” Cells 9, no. 4 (2020): 880.

[332] E. A. Littlejohn and S. U. Monrad, “Early Diagnosis and Treatment of Rheumatoid Arthritis,” Primary Care 45, no. 2 (2018): 237–255.

[333] S. Alivernini, G. S. Firestein, and I. B. McInnes, “The Pathogenesis of Rheumatoid Arthritis,” Immunity 55, no. 12 (2022): 2255–2270.

[334] N. Kondo, T. Kuroda, and D. Kobayashi, “Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis,” International Journal of Molecular Sciences 22, no. 20 (2021): 10922.

[335] P. Ye, X. Chi, J. H. Cha, et al., “Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges,” Cells 10, no. 12 (2021): 3309.

[336] W. Wang, T. Xiang, Y. Yang, Z. Wang, and J. Xie, “E3 ubiquitin Ligases STUB1/CHIP Contributes to the Th17/Treg Imbalance via the Ubiquitination of Aryl Hydrocarbon Receptor in Rheumatoid Arthritis,” Clinical and Experimental Immunology 209, no. 3 (2022): 280–290.

[337] W. Wang, Y. Yang, Y. Shi, T. Xiang, and J. Xie, “E3 ubiquitin Ligase STUB1 Affects the mTORC1 Pathway Through p62 and Participates in Regulating the Differentiation of Follicular Helper T Cells in Rheumatoid Arthritis,” Clinical Immunology 255 (2023): 109736.

[338] Y. Liu, H. Zhou, and X. Tang, “STUB1/CHIP: New Insights in Cancer and Immunity,” Biomedicine & Pharmacotherapy 165 (2023): 115190.

[339] N. Saeki, K. Inoue, M. Ideta-Otsuka, et al., “Epigenetic Regulator UHRF1 Orchestrates Proinflammatory Gene Expression in Rheumatoid Arthritis in a Suppressive Manner,” Journal of Clinical Investigation 132, no. 11 (2022): e150533.

[340] M. Bostick, J. K. Kim, P. O. Esteve, A. Clark, S. Pradhan, and S. E. Jacobsen, “UHRF1 plays a Role in Maintaining DNA Methylation in Mammalian Cells,” Science 317, no. 5845 (2007): 1760–1764.

[341] K. Arita, S. Isogai, T. Oda, et al., “Recognition of Modification Status on a Histone H3 Tail by Linked Histone Reader Modules of the Epigenetic Regulator UHRF1,” PNAS 109, no. 32 (2012): 12950–12955.

[342] H. Zhang, Q. Gao, S. Tan, et al., “SET8 prevents Excessive DNA Methylation by Methylation-mediated Degradation of UHRF1 and DNMT1,” Nucleic Acids Res 47, no. 17 (2019): 9053–9068.

[343] L. Lin, Z. Huang, W. Li, et al., “Mid1 promotes Synovitis in Rheumatoid Arthritis via Ubiquitin-dependent Post-translational Modification,” Pharmacological Research 205 (2024): 107224.

[344] N. Lukac, D. Flegar, S. Priselac, et al., “Midline 1 Associated With Fas Signaling Enhances Murine Antigen-induced Arthritis,” Frontiers in Cell and Developmental Biology 13 (2025): 1451093.

[345] D. C. Rubin, A. Shaker, and M. S. Levin, “Chronic Intestinal Inflammation: Inflammatory Bowel Disease and Colitis-associated Colon Cancer,” Frontiers in immunology 3 (2012): 107.

[346] J. Davis and R. Kellerman, “Gastrointestinal Conditions: Inflammatory Bowel Disease,” FP Essent 516 (2022): 23–30.

[347] G. P. Ramos and K. A. Papadakis, “Mechanisms of Disease: Inflammatory Bowel Diseases,” Mayo Clinic Proceedings 94, no. 1 (2019): 155–165.

[348] K. Fujimoto, M. Kinoshita, H. Tanaka, et al., “Regulation of Intestinal Homeostasis by the Ulcerative Colitis-associated Gene RNF186,” Mucosal Immunol 10, no. 2 (2017): 446–459.

[349] M. Beaudoin, P. Goyette, G. Boucher, et al., “Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated With Ulcerative Colitis,” PLos Genet 9, no. 9 (2013): e1003723.

[350] H. Zhang, Z. Cui, D. Cheng, et al., “RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced Autophagy in the Colonic Epithelial Cells for the Maintenance of Intestinal Homeostasis,” Autophagy 17, no. 10 (2021): 3030–3047.

[351] K. Ranjan, M. Hedl, S. Sinha, X. Zhang, and C. Abraham, “Ubiquitination of ATF6 by Disease-associated RNF186 Promotes the Innate Receptor-induced Unfolded Protein Response,” Journal of Clinical Investigation 131, no. 17 (2021): e145472.

[352] K. Ranjan, M. Hedl, and C. Abraham, “The E3 Ubiquitin Ligase RNF186 and RNF186 Risk Variants Regulate Innate Receptor-induced Outcomes,” PNAS 118, no. 32 (2021): e2013500118.

[353] M. A. Rivas, D. Graham, P. Sulem, et al., “A Protein-truncating R179X Variant in RNF186 Confers Protection Against Ulcerative Colitis,” Nature Communications 7 (2016): 12342.

[354] K. Chathuranga, P. Rathnapala, A. Weerawardhana, et al., “The E3 Ubiquitin Ligase MARCH2 Controls TNF-alpha Mediated Inflammation by Autoubiquitination,” Cell Communication and Signaling 23, no. 1 (2025): 257.

[355] X. Li, Q. Li, B. Xiong, H. Chen, X. Wang, and D. Zhang, “Discoidin Domain Receptor 1(DDR1) Promote Intestinal Barrier Disruption in Ulcerative Colitis Through Tight Junction Proteins Degradation and Epithelium Apoptosis,” Pharmacological Research 183 (2022): 106368.

[356] S. Li, A. Zhuge, K. Wang, et al., “Ketogenic Diet Aggravates Colitis, Impairs Intestinal Barrier and Alters Gut Microbiota and Metabolism in DSS-induced Mice,” Food Funct 12, no. 20 (2021): 10210–10225.

[357] K. Chathuranga, T. H. Kim, H. Lee, et al., “Negative Regulation of NEMO Signaling by the Ubiquitin E3 Ligase MARCH2,” Embo Journal 39, no. 21 (2020): e105139.

[358] R. Li, C. Chen, J. He, et al., “E3 ligase ASB8 Promotes Porcine Reproductive and respiratory Syndrome Virus Proliferation by Stabilizing the Viral Nsp1alpha Protein and Degrading Host IKKbeta Kinase,” Virology 532 (2019): 55–68.

[359] M. Cheng, B. Xu, Y. Sun, et al., “ASB3 expression Aggravates Inflammatory Bowel Disease by Targeting TRAF6 Protein Stability and Affecting the Intestinal Microbiota,” MBio 15, no. 9 (2024): e0204324.

[360] M. Filippi, A. Bar-Or, F. Piehl, et al., “Multiple Sclerosis,” Nature reviews Disease primers 4, no. 1 (2018): 43.

[361] Y. Xu, F. Zhao, Q. Qiu, et al., “The ER Membrane-anchored Ubiquitin Ligase Hrd1 Is a Positive Regulator of T-cell Immunity,” Nature Communications 7 (2016): 12073.

[362] Q. Zeng, H. Guo, N. Tang, et al., “K27-linked RORgammat Ubiquitination by Nedd4 Potentiates Th17-mediated Autoimmunity,” Journal of Biomedical Science 32, no. 1 (2025): 26.

[363] P. Wang, J. Zhao, Y. Tan, et al., “RNF157 attenuates CD4(+) T Cell-mediated Autoimmune Response by Promoting HDAC1 Ubiquitination and Degradation,” Theranostics 13, no. 11 (2023): 3509–3523.

[364] I. I. Ivanov, B. S. McKenzie, L. Zhou, et al., “The Orphan Nuclear Receptor RORgammat Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells,” Cell 126, no. 6 (2006): 1121–1133.

[365] X. Yang, X. Zhu, J. Sheng, et al., “RNF213 promotes Treg Cell Differentiation by Facilitating K63-linked Ubiquitination and Nuclear Translocation of FOXO1,” Nature Communications 15, no. 1 (2024): 5961.

[366] W. Ouyang, O. Beckett, Q. Ma, J. H. Paik, R. A. DePinho, and L. I. MO, “Foxo Proteins Cooperatively Control the Differentiation of Foxp3+ Regulatory T Cells,” Nature Immunology 11, no. 7 (2010): 618–627.

[367] Y. Wei, W. Li, J. Huang, et al., “Midline-1 Regulates Effector T Cell Motility in Experimental Autoimmune Encephalomyelitis via mTOR/Microtubule Pathway,” Theranostics 14, no. 3 (2024): 1168–1180.

[368] K. H. Sturner, U. Borgmeyer, C. Schulze, O. Pless, and R. Martin, “A Multiple Sclerosis-associated Variant of CBLB Links Genetic Risk With Type I IFN Function,” Journal of Immunology 193, no. 9 (2014): 4439–4447.

[369] S. Sanna, M. Pitzalis, M. Zoledziewska, et al., “Variants Within the Immunoregulatory CBLB Gene Are Associated With Multiple Sclerosis,” Nature Genetics 42, no. 6 (2010): 495–497.

[370] S. Peer, G. Cappellano, N. Hermann-Kleiter, et al., “Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b,” Frontiers in immunology 9 (2018): 2311.

[371] J. Han, R. Hong, C. Cao, et al., “CXCL13 Damages Blood Spinal Cord Barrier by Promoting RNF6/Sqstm1-Ubiquitination Induced Autophagy in Experimental Allergic Encephalomyelitis,” Adv Sci (Weinh) 12, no. 21 (2025): e2414550.

[372] A. Kaushik, S. Parashar, R. K. Ambasta, and P. Kumar, “Ubiquitin E3 Ligases Assisted Technologies in Protein Degradation: Sharing Pathways in Neurodegenerative Disorders and Cancer,” Ageing Research Reviews 96 (2024): 102279.

[373] L. Yang, C. Hu, X. Chen, et al., “Upregulated Expression of Ubiquitin Ligase TRIM21 Promotes PKM2 Nuclear Translocation and Astrocyte Activation in Experimental Autoimmune Encephalomyelitis,” Elife 13 (2024): RP98181.

[374] Y. Wu, R. Gao, Q. Huang, et al., “Lactate Supplementation After Hypoglycemia Alleviates Cognitive Dysfunction Induced by Recurrent Non-severe Hypoglycemia in Diabetic Mice,” Experimental Neurology 383 (2025): 115037.

[375] L. Yang, C. Hu, X. Chen, et al., “Ubiquitination-mediated Upregulation of Glycolytic Enzyme MCT4 in Promoting Astrocyte Reactivity During Neuroinflammation,” J Neuroinflammation 22, no. 1 (2025): 126.

[376] H. Vargas-Uricoechea, “Molecular Mechanisms in Autoimmune Thyroid Disease,” Cells 12, no. 6 (2023): 918.

[377] P. Petranović Ovčariček, R. Görges, and L. Giovanella, “Autoimmune Thyroid Diseases,” Seminars in Nuclear Medicine 54, no. 2 (2024): 219–236.

[378] Z. Jiang, H. Cai, Y. Lin, R. Lin, L. Chen, and H. Huang, “T-cell Exhaustion-related Genes in Graves' disease: A Comprehensive Genome Mapping Analysis,” Front Endocrinol (Lausanne) 15 (2024): 1364782.

[379] R. H. Song, Z. Y. Yu, Q. Wang, et al., “Polymorphisms of the TNFAIP3 Region and Graves' disease,” Autoimmunity 47, no. 7 (2014): 459–465.

[380] N. J. Korman, “Management of Psoriasis as a Systemic Disease: What Is the Evidence?,” British Journal of Dermatology 182, no. 4 (2020): 840–848.

[381] C. E. Griffiths and J. N. Barker, “Pathogenesis and Clinical Features of Psoriasis,” Lancet 370, no. 9583 (2007): 263–271.

[382] M. J. Bijlmakers, S. K. Kanneganti, J. N. Barker, R. C. Trembath, and F. Capon, “Functional Analysis of the RNF114 Psoriasis Susceptibility Gene Implicates Innate Immune Responses to Double-stranded RNA in Disease Pathogenesis,” Human Molecular Genetics 20, no. 16 (2011): 3129–3137.

[383] F. Capon, M. J. Bijlmakers, N. Wolf, et al., “Identification of ZNF313/RNF114 as a Novel Psoriasis Susceptibility Gene,” Human Molecular Genetics 17, no. 13 (2008): 1938–1945.

[384] P. Harirchian, J. Lee, S. Hilz, et al., “A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program With a Shared Single-Cell Expression Signature in Diverse Human Rashes,” Journal of Investigative Dermatology 139, no. 6 (2019): 1264–1273.

[385] Z. Su, S. A. Dziedzic, D. Hu, et al., “ABIN-1 Heterozygosity Sensitizes to Innate Immune Response in both RIPK1-dependent and RIPK1-independent Manner,” Cell Death and Differentiation 26, no. 6 (2019): 1077–1088.

[386] H. Liu, W. Lin, Z. Liu, et al., “E3 ubiquitin Ligase NEDD4L Negatively Regulates Keratinocyte Hyperplasia by Promoting GP130 Degradation,” Embo Reports 22, no. 5 (2021): e52063.

[387] N. Wang, X. Xu, F. Guan, et al., “FGF12 Positively Regulates Keratinocyte Proliferation by Stabilizing MDM2 and Inhibiting p53 Activity in Psoriasis,” Adv Sci (Weinh) 11, no. 39 (2024): e2400107.

[388] P. A. O'Sullivan, A. Aidarova, I. S. Afonina, et al., “CARD14 signalosome Formation Is Associated With Its Endosomal Relocation and mTORC1-induced Keratinocyte Proliferation,” Biochemical Journal 481, no. 18 (2024): 1143–1171.

[389] L. Yang, T. Zhang, C. Zhang, C. Xiao, X. Bai, and G. Wang, “Upregulated E3 Ligase Tripartite Motif-containing Protein 21 in Psoriatic Epidermis Ubiquitylates Nuclear Factor-kappaB p65 Subunit and Promotes Inflammation in Keratinocytes,” British Journal of Dermatology 184, no. 1 (2021): 111–122.

[390] L. Yang, L. Jin, and Y. Ke, “E3 Ligase Trim21 Ubiquitylates and Stabilizes Keratin 17 to Induce STAT3 Activation in Psoriasis,” Journal of Investigative Dermatology 138, no. 12 (2018): 2568–2577.

[391] J. Zhang, J. Zhu, X. Chen, H. Xia, and L. Yang, “E3 ubiquitin Ligase Trim33 Ubiquitylates Annexin A2 to Promote NF-kappaB Induced Skin Inflammation in Psoriasis,” Journal of Dermatological Science 107, no. 3 (2022): 160–168.

[392] L. Yang, J. Zhang, C. Hu, et al., “Nuclear Translocation of PKM2 Mediates Keratinocyte Metabolic Reprogramming in Psoriasis,” Experimental Dermatology 32, no. 11 (2023): 1960–1970.

[393] M. Roy, K. Singh, A. Shinde, et al., “TNF-alpha-induced E3 Ligase, TRIM15 Inhibits TNF-alpha-regulated NF-kappaB Pathway by Promoting Turnover of K63 Linked Ubiquitination of TAK1,” Cell Signalling 91 (2022): 110210.

[394] S. K. Kim, “The Mechanism of the NLRP3 Inflammasome Activation and Pathogenic Implication in the Pathogenesis of Gout,” J Rheum Dis 29, no. 3 (2022): 140–153.

[395] Y. R. Liu, J. Q. Wang, and J. Li, “Role of NLRP3 in the Pathogenesis and Treatment of Gout Arthritis,” Frontiers in immunology 14 (2023): 1137822.

[396] X. Zhan, Q. Li, G. Xu, X. Xiao, and Z. Bai, “The Mechanism of NLRP3 Inflammasome Activation and Its Pharmacological Inhibitors,” Frontiers in immunology 13 (2022): 1109938.

[397] X. Xu and H. Qiu, “BRD4 promotes Gouty Arthritis Through MDM2-mediated PPARgamma Degradation and Pyroptosis,” Molecular Medicine 30, no. 1 (2024): 67.

[398] X. Qu, Q. Wang, and H. Qiu, “S-nitrosylated NEDD4 Exacerbates Gouty Arthritis by Upregulating NOD1 to Induce Pyroptosis,” Genes and Immunity 26, no. 4 (2025): 365–375.

[399] Y. Lin, X. Lv, C. Sun, et al., “TRIM50 promotes NLRP3 Inflammasome Activation by Directly Inducing NLRP3 Oligomerization,” Embo Reports 23, no. 11 (2022): e54569.

[400] D. Song, X. Zhou, Q. Yu, R. Li, Q. Dai, and M. Zeng, “ML335 inhibits TWIK2 Channel-mediated Potassium Efflux and Attenuates Mitochondrial Damage in MSU Crystal-induced Inflammation,” Journal of translational medicine 22, no. 1 (2024): 785.

[401] A. K. Singh, M. Haque, K. O'Sullivan, M. Chourasia, M. M. Ouseph, and S. Ahmed, “Suppression of Monosodium Urate Crystal-induced Inflammation by Inhibiting TGF-beta-activated Kinase 1-dependent Signaling: Role of the Ubiquitin Proteasome System,” Cell Mol Immunol 18, no. 1 (2021): 162–170.

[402] Z. Cheng, M. Huang, W. Li, et al., “HECTD3 inhibits NLRP3 Inflammasome Assembly and Activation by Blocking NLRP3-NEK7 Interaction,” Cell death & disease 15, no. 1 (2024): 86.

[403] H. Zhang, X. D. Zhou, M. D. Shapiro, et al., “Global Burden of Metabolic Diseases, 1990–2021,” Metabolism 160 (2024): 155999.

[404] J. J. Noubiap, J. R. Nansseu, E. Lontchi-Yimagou, et al., “Geographic Distribution of Metabolic Syndrome and Its Components in the General Adult Population: A Meta-analysis of Global Data From 28 Million Individuals,” Diabetes Research and Clinical Practice 188 (2022): 109924.

[405] K. C. Pao, N. T. Wood, A. Knebel, et al., “Activity-based E3 Ligase Profiling Uncovers an E3 Ligase With Esterification Activity,” Nature 556, no. 7701 (2018): 381–385.

[406] A. M. K. Rothman, A. Florentin, F. Zink, et al., “Therapeutic Potential of Allosteric HECT E3 Ligase Inhibition,” Cell 188, no. 10 (2025): 2603–2620. e18.

[407] H. Yi, H. Shi, W. Mao, et al., “E3 ubiquitin Ligase IPI1 Controls Rice Immunity and Flowering via both E3 Ligase-dependent and -independent Pathways,” Developmental Cell 59, no. 20 (2024): 2719–2730. e4.

[408] D. L. Haakonsen, M. Heider, A. J. Ingersoll, et al., “Stress Response Silencing by an E3 Ligase Mutated in Neurodegeneration,” Nature 626, no. 8000 (2024): 874–880.

[409] F. Scheufele, B. Wolf, M. Kruse, et al., “Evidence for a Regulatory Role of Cullin-RING E3 Ubiquitin Ligase 7 in Insulin Signaling,” Cell Signalling 26, no. 2 (2014): 233–239.

[410] X. Xu, M. Keshwani, K. Meyer, A. Sarikas, S. Taylor, and Z. Q. Pan, “Identification of the Degradation Determinants of Insulin Receptor Substrate 1 for Signaling Cullin-RING E3 Ubiquitin Ligase 7-mediated Ubiquitination,” Journal of Biological Chemistry 287, no. 48 (2012): 40758–40766.

[411] H. Lee, J. J. Park, N. Nguyen, et al., “MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle,” Journal of Biological Chemistry 291, no. 52 (2016): 26627–26635.

[412] J. S. Park, H. Lee, B. W. Choi, et al., “An MG53-IRS1-interaction Disruptor Ameliorates Insulin Resistance,” Experimental & Molecular Medicine 50, no. 6 (2018): 1–12.

[413] S. Thakur, P. Rawat, B. Dehury, and P. Mondal, “TRIM32 regulates Insulin Sensitivity by Controlling Insulin Receptor Degradation in the Liver,” Embo Reports 26, no. 3 (2025): 791–809.

[414] T. Wan, Y. Wang, C. Wang, H. Wang, X. Li, and Y. Li, “Overexpression of TRIM32 Promotes Pancreatic Beta-cell Autophagic Cell Death Through Akt/mTOR Pathway Under High Glucose Conditions,” Cell Biology International 46, no. 12 (2022): 2095–2106.

[415] J. C. Molero, T. E. Jensen, P. C. Withers, et al., “c-Cbl-deficient Mice Have Reduced Adiposity, Higher Energy Expenditure, and Improved Peripheral Insulin Action,” Journal of Clinical Investigation 114, no. 9 (2004): 1326–1333.

[416] J. Liu, A. Kimura, C. A. Baumann, and A. R. Saltiel, “APS Facilitates c-Cbl Tyrosine Phosphorylation and GLUT4 Translocation in Response to Insulin in 3T3-L1 Adipocytes,” Molecular and Cellular Biology 22, no. 11 (2002): 3599–3609.

[417] K. D. D. Gorrepati, W. He, B. Lupse, T. Yuan, K. Maedler, and A. Ardestani, “An SCF(FBXO28) E3 Ligase Protects Pancreatic β-Cells From Apoptosis,” International Journal of Molecular Sciences 19, no. 4 (2018): 975.

[418] A. Loregger, E. C. Cook, J. K. Nelson, et al., “A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis From Lipoprotein Uptake in Hepatocytes,” Molecular and Cellular Biology 36, no. 2 (2016): 285–294.

[419] T. N. Dang, J. L. Taylor, G. Kilroy, Y. Yu, D. H. Burk, and Z. E. Floyd, “SIAH2 is Expressed in Adipocyte Precursor Cells and Interacts With EBF1 and ZFP521 to Promote Adipogenesis,” Obesity (Silver Spring) 29, no. 1 (2021): 98–107.

[420] Y. G. Jeon, H. Nahmgoong, J. Oh, et al., “Ubiquitin Ligase RNF20 Coordinates Sequential Adipose Thermogenesis With Brown and Beige Fat-specific Substrates,” Nature Communications 15, no. 1 (2024): 940.

[421] H. Qin, Y. Zhong, J. Huang, Y. Miao, M. Du, and K. Huang, “TRIM56 Promotes White Adipose Tissue Browning to Attenuate Obesity by Degrading TLE3,” Adv Sci (Weinh) 12, no. 13 (2025): e2414073.

[422] P. Wei, D. Pan, C. Mao, and Y. X. Wang, “RNF34 is a Cold-regulated E3 Ubiquitin Ligase for PGC-1alpha and Modulates Brown Fat Cell Metabolism,” Molecular and Cellular Biology 32, no. 2 (2012): 266–275.

[423] I. Onoyama, A. Suzuki, A. Matsumoto, et al., “Fbxw7 regulates Lipid Metabolism and Cell Fate Decisions in the Mouse Liver,” Journal of Clinical Investigation 121, no. 1 (2011): 342–354.

[424] M. T. Bengoechea-Alonso and J. Ericsson, “The Ubiquitin Ligase Fbxw7 Controls Adipocyte Differentiation by Targeting C/EBPalpha for Degradation,” PNAS 107, no. 26 (2010): 11817–11822.

[425] R. Menghini, L. Hoyles, M. Cardellini, et al., “ITCH E3 Ubiquitin Ligase Downregulation Compromises Hepatic Degradation of Branched-chain Amino Acids,” Mol Metab 59 (2022): 101454.

[426] C. Wang, W. Xu, Y. Chao, M. Liang, F. Zhang, and K. Huang, “E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis,” Adv Sci (Weinh) 7, no. 20 (2020): 2001800.

[427] H. Walden and R. J. Martinez-Torres, “Regulation of Parkin E3 Ubiquitin Ligase Activity,” Cellular and Molecular Life Sciences 69, no. 18 (2012): 3053–3067.

[428] E. Rubio de la Torre, P. Gómez-Suaga, M. Martínez-Salvador, and S. Hilfiker, “Posttranslational Modifications as Versatile Regulators of Parkin Function,” Current Medicinal Chemistry 18, no. 16 (2011): 2477–2485.

[429] J. Prudent, R. Zunino, A. Sugiura, S. Mattie, G. C. Shore, and H. M. McBride, “MAPL SUMOylation of Drp1 Stabilizes an ER/Mitochondrial Platform Required for Cell Death,” Molecular Cell 59, no. 6 (2015): 941–955.

[430] R. Puri, X. T. Cheng, M. Y. Lin, N. Huang, and Z. H. Sheng, “Defending Stressed Mitochondria: Uncovering the Role of MUL1 in Suppressing Neuronal Mitophagy,” Autophagy 16, no. 1 (2020): 176–178.

[431] I. Shiiba, K. Takeda, S. Nagashima, and S. Yanagi, “Overview of Mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5 From Molecular Mechanisms to Diseases,” International Journal of Molecular Sciences 21, no. 11 (2020): 3781.

[432] H. J. Kim, Y. Nagano, S. J. Choi, et al., “HDAC6 maintains Mitochondrial Connectivity Under Hypoxic Stress by Suppressing MARCH5/MITOL Dependent MFN2 Degradation,” Biochemical and Biophysical Research Communications 464, no. 4 (2015): 1235–1240.

[433] Z. Chen, L. Liu, Q. Cheng, et al., “Mitochondrial E3 Ligase MARCH5 Regulates FUNDC1 to Fine-tune Hypoxic Mitophagy,” Embo Reports 18, no. 3 (2017): 495–509.

[434] S. Bisht and M. F. Singh, “The Triggering Pathway, the Metabolic Amplifying Pathway, and Cellular Transduction in Regulation of Glucose-dependent Biphasic Insulin Secretion,” Archives of Physiology and Biochemistry 130, no. 6 (2024): 854–865.

[435] L. Norton, C. Shannon, A. Gastaldelli, and R. A. DeFronzo, “Insulin: The Master Regulator of Glucose Metabolism,” Metabolism 129 (2022): 155142.

[436] A. R. Saltiel, “Insulin Signaling in the Control of Glucose and Lipid Homeostasis,” Handb Exp Pharmacol 233 (2016): 51–71.

[437] X. D. Yang, D. X. Xiang, and Y. Y. Yang, “Role of E3 Ubiquitin Ligases in Insulin Resistance,” Diabetes, Obesity & Metabolism 18, no. 8 (2016): 747–754.

[438] X. Hou, Y. Chen, B. Zhou, et al., “Talin-1 Inhibits Smurf1-mediated Stat3 Degradation to Modulate Beta-cell Proliferation and Mass in Mice,” Cell death & disease 14, no. 10 (2023): 709.

[439] J. S. Yi, J. S. Park, Y. M. Ham, et al., “MG53-induced IRS-1 Ubiquitination Negatively Regulates Skeletal Myogenesis and Insulin Signalling,” Nature Communications 4 (2013): 2354.

[440] X. Xu, A. Sarikas, D. C. Dias-Santagata, et al., “The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-dependent Degradation,” Molecular Cell 30, no. 4 (2008): 403–414.

[441] C. Bianchi, F. Raggi, C. Rossi, et al., “MG53 marks Poor Beta Cell Performance and Predicts Onset of Type 2 Diabetes in Subjects With Different Degrees of Glucose Tolerance,” Diabetes & Metabolism 48, no. 2 (2022): 101292.

[442] T. Cardozo and M. Pagano, “The SCF Ubiquitin Ligase: Insights Into a Molecular Machine,” Nature Reviews Molecular Cell Biology 5, no. 9 (2004): 739–751.

[443] N. A. Scott, L. J. Sharpe, and A. J. Brown, “The E3 Ubiquitin Ligase MARCHF6 as a Metabolic Integrator in Cholesterol Synthesis and Beyond,” Biochim Biophys Acta Mol Cell Biol Lipids 1866, no. 1 (2021): 158837.

[444] G. Kilroy, D. H. Burk, and Z. E. Floyd, “Siah2 Protein Mediates Early Events in Commitment to an Adipogenic Pathway,” Journal of Biological Chemistry 291, no. 53 (2016): 27289–27297.

[445] G. Kilroy, H. Kirk-Ballard, L. E. Carter, and Z. E. Floyd, “The Ubiquitin Ligase Siah2 Regulates PPARgamma Activity in Adipocytes,” Endocrinology 153, no. 3 (2012): 1206–1218.

[446] J. A. Haley, C. Jang, and D. A. Guertin, “A New Era of Understanding in Vivo Metabolic Flux in Thermogenic Adipocytes,” Current opinion in genetics & development 83 (2023): 102112.

[447] A. A. van der Lans, J. Hoeks, B. Brans, et al., “Cold Acclimation Recruits human Brown Fat and Increases Nonshivering Thermogenesis,” Journal of Clinical Investigation 123, no. 8 (2013): 3395–3403.

[448] J. Yu, X. Gu, Y. Guo, et al., “E3 ligase FBXW7 Suppresses Brown Fat Expansion and Browning of White Fat,” Embo Reports 26, no. 3 (2025): 748–767.

[449] H. Zhao, F. Zhang, D. Sun, et al., “Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling,” Diabetes 69, no. 6 (2020): 1164–1177.

[450] O. Rothfuss, H. Fischer, T. Hasegawa, et al., “Parkin Protects Mitochondrial Genome Integrity and Supports Mitochondrial DNA Repair,” Human Molecular Genetics 18, no. 20 (2009): 3832–3850.

[451] G. Gouspillou, R. Godin, J. Piquereau, et al., “Protective Role of Parkin in Skeletal Muscle Contractile and Mitochondrial Function,” The Journal of Physiology 596, no. 13 (2018): 2565–2579.

[452] A. Okuzumi, T. Hatano, S. I. Ueno, et al., “Metabolomics-based Identification of Metabolic Alterations in PARK2,” Ann Clin Transl Neurol 6, no. 3 (2019): 525–536.

[453] L. Hang, J. Thundyil, G. W. Y. Goh, and K. L. Lim, “AMP Kinase Activation Is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression,” Neuromolecular Med 21, no. 1 (2019): 25–32.

[454] J. Peng, K. D. Ren, J. Yang, and X. J. Luo, “Mitochondrial E3 Ubiquitin Ligase 1: A Key Enzyme in Regulation of Mitochondrial Dynamics and Functions,” Mitochondrion 28 (2016): 49–53.

[455] L. Scorrano and D. Liu, “The SUMO Arena Goes Mitochondrial With MAPL,” Embo Reports 10, no. 7 (2009): 694–696.

[456] S. Y. Kim, H. J. Kim, S. U. Kang, et al., “Non-thermal Plasma Induces AKT Degradation Through Turn-on the MUL1 E3 Ligase in Head and Neck Cancer,” Oncotarget 6, no. 32 (2015): 33382–33396.

[457] M. S. Lee, S. O. Lee, J. Choi, et al., “MUL1-RING Recruits the Substrate, p53-TAD as a Complex With UBE2D2-UB Conjugate,” Febs Journal 289, no. 12 (2022): 3568–3586.

[458] J. Li, W. Qi, G. Chen, et al., “Mitochondrial Outer-membrane E3 Ligase MUL1 Ubiquitinates ULK1 and Regulates Selenite-induced Mitophagy,” Autophagy 11, no. 8 (2015): 1216–1229.

[459] S. Nagashima, N. Ito, I. Shiiba, H. Shimura, and S. Yanagi, “Ubiquitin-mediated Mitochondrial Regulation by MITOL/MARCHF5 at a Glance,” Journal of Biochemistry 173, no. 1 (2022): 1–11.

[460] R. Yonashiro, S. Ishido, S. Kyo, et al., “A Novel Mitochondrial Ubiquitin Ligase Plays a Critical Role in Mitochondrial Dynamics,” Embo Journal 25, no. 15 (2006): 3618–3626.

[461] N. Nakamura, Y. Kimura, M. Tokuda, S. Honda, and S. Hirose, “MARCH-V Is a Novel Mitofusin 2- and Drp1-binding Protein Able to Change Mitochondrial Morphology,” Embo Reports 7, no. 10 (2006): 1019–1022.

[462] S. Xu, E. Cherok, S. Das, et al., “Mitochondrial E3 Ubiquitin Ligase MARCH5 Controls Mitochondrial Fission and Cell Sensitivity to Stress-induced Apoptosis Through Regulation of MiD49 Protein,” Molecular Biology of the Cell 27, no. 2 (2016): 349–359.

[463] V. Choudhary, I. Kaddour-Djebbar, R. Alaisami, M. V. Kumar, and W. B. Bollag, “Mitofusin 1 Degradation Is Induced by a Disruptor of Mitochondrial Calcium Homeostasis, CGP37157: A Role in Apoptosis in Prostate Cancer Cells,” International Journal of Oncology 44, no. 5 (2014): 1767–1773.

[464] A. Sugiura, R. Yonashiro, T. Fukuda, et al., “A Mitochondrial Ubiquitin Ligase MITOL Controls Cell Toxicity of Polyglutamine-expanded Protein,” Mitochondrion 11, no. 1 (2011): 139–146.

[465] R. Yonashiro, A. Sugiura, M. Miyachi, et al., “Mitochondrial Ubiquitin Ligase MITOL Ubiquitinates Mutant SOD1 and Attenuates Mutant SOD1-induced Reactive Oxygen Species Generation,” Molecular Biology of the Cell 20, no. 21 (2009): 4524–4530.

[466] F. Koyano, K. Yamano, H. Kosako, K. Tanaka, and N. Matsuda, “Parkin Recruitment to Impaired Mitochondria for Nonselective Ubiquitylation Is Facilitated by MITOL,” Journal of Biological Chemistry 294, no. 26 (2019): 10300–10314.

[467] A. Sugiura, S. Nagashima, T. Tokuyama, et al., “MITOL Regulates Endoplasmic Reticulum-mitochondria Contacts via Mitofusin2,” Molecular Cell 51, no. 1 (2013): 20–34.

[468] M. A. DeTure and D. W. Dickson, “The Neuropathological Diagnosis of Alzheimer's Disease,” Mol Neurodegener 14, no. 1 (2019): 32.

[469] R. Balestrino and A. H. V. Schapira, “Parkinson Disease,” European Journal of Neurology 27, no. 1 (2020): 27–42.

[470] D. M. Wilson 3rd, M. R. Cookson, L. Van Den Bosch, H. Zetterberg, D. M. Holtzman, and I. Dewachter, “Hallmarks of Neurodegenerative Diseases,” Cell 186, no. 4 (2023): 693–714.

[471] A. Opattova, M. Cente, M. Novak, and P. Filipcik, “The Ubiquitin Proteasome System as a Potential Therapeutic Target for Treatment of Neurodegenerative Diseases,” General Physiology and Biophysics 34, no. 4 (2015): 337–352.

[472] B. R. Whatley, L. Li, and L. S. Chin, “The Ubiquitin-proteasome System in Spongiform Degenerative Disorders,” Biochimica Et Biophysica Acta 1782, no. 12 (2008): 700–712.

[473] C. Soto and S. Pritzkow, “Protein Misfolding, Aggregation, and Conformational Strains in Neurodegenerative Diseases,” Nature Neuroscience 21, no. 10 (2018): 1332–1340.

[474] F. W. van Leeuwen, E. M. Hol, and D. F. Fischer, “Frameshift Proteins in Alzheimer's Disease and in Other Conformational Disorders: Time for the Ubiquitin-proteasome System,” Journal of Alzheimer's Disease 9, no. 3 (2006): 319–325. Suppl.

[475] B. Gong, M. Radulovic, M. E. Figueiredo-Pereira, and C. Cardozo, “The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer's Disease and Spinal Cord Injury,” Front Mol Neurosci 9 (2016): 4.

[476] T. M. Dawson and V. L. Dawson, “The Role of Parkin in Familial and Sporadic Parkinson's Disease,” Movement Disorders 25, no. Suppl 1 (2010): S32–39. 0 1.

[477] G. M. Cole and P. S. Timiras, “Ubiquitin-protein Conjugates in Alzheimer's Lesions,” Neuroscience Letters 79, no. 1-2 (1987): 207–212.

[478] A. Ciechanover and Y. T. Kwon, “Degradation of Misfolded Proteins in Neurodegenerative Diseases: Therapeutic Targets and Strategies,” Experimental & Molecular Medicine 47, no. 3 (2015): e147.

[479] O. Karayel, A. Soung, H. Gurung, et al., “Impairment of DET1 Causes Neurological Defects and Lethality in Mice and Humans,” PNAS 122, no. 7 (2025): e2422631122.

[480] T. R. Cotton, S. A. Cobbold, J. P. Bernardini, L. W. Richardson, X. S. Wang, and B. C. Lechtenberg, “Structural Basis of K63-ubiquitin Chain Formation by the Gordon-Holmes Syndrome RBR E3 Ubiquitin Ligase RNF216,” Molecular Cell 82, no. 3 (2022): 598–615. e8.

[481] M. C. Ambrozkiewicz and H. Kawabe, “HECT-type E3 Ubiquitin Ligases in Nerve Cell Development and Synapse Physiology,” Febs Letters 589, no. 14 (2015): 1635–1643.

[482] H. Kawabe and J. Stegmuller, “The Role of E3 Ubiquitin Ligases in Synapse Function in the Healthy and Diseased Brain,” Molecular and Cellular Neuroscience 112 (2021): 103602.

[483] A. N. Hegde and S. C. Upadhya, “The Ubiquitin-proteasome Pathway in Health and Disease of the Nervous System,” Trends in Neuroscience (Tins) 30, no. 11 (2007): 587–595.

[484] A. N. Hegde, “The Ubiquitin-proteasome Pathway and Synaptic Plasticity,” Learning & Memory (Cold Spring Harbor, NY) 17, no. 7 (2010): 314–327.

[485] A. J. George, Y. C. Hoffiz, A. J. Charles, Y. Zhu, and A. M. Mabb, “A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders,” Frontiers in Genetics 9 (2018): 29.

[486] C. Themistokleous, E. Bagnoli, R. Parulekar, and M. M. K. Muqit, “Role of Autophagy Pathway in Parkinson's Disease and Related Genetic Neurological Disorders,” Journal of Molecular Biology 435, no. 12 (2023): 168144.

[487] F. Bonello, S. M. Hassoun, F. Mouton-Liger, et al., “LRRK2 impairs PINK1/Parkin-dependent Mitophagy via Its Kinase Activity: Pathologic Insights Into Parkinson's Disease,” Human Molecular Genetics 28, no. 10 (2019): 1645–1660.

[488] D. Yao, Z. Gu, T. Nakamura, et al., “Nitrosative Stress Linked to Sporadic Parkinson's Disease: S-nitrosylation of Parkin Regulates Its E3 Ubiquitin Ligase Activity,” PNAS 101, no. 29 (2004): 10810–10814.

[489] V. S. Burchell, D. E. Nelson, A. Sanchez-Martinez, et al., “The Parkinson's Disease-linked Proteins Fbxo7 and Parkin Interact to Mediate Mitophagy,” Nature Neuroscience 16, no. 9 (2013): 1257–1265.

[490] H. S. Ko, R. Bailey, W. W. Smith, et al., “CHIP Regulates Leucine-rich Repeat Kinase-2 Ubiquitination, Degradation, and Toxicity,” PNAS 106, no. 8 (2009): 2897–2902.

[491] X. Ding and M. S. Goldberg, “Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP,” PLoS ONE 4, no. 6 (2009): e5949.

[492] J. T. Lee, T. C. Wheeler, L. Li, and L. S. Chin, “Ubiquitination of Alpha-synuclein by Siah-1 Promotes Alpha-synuclein Aggregation and Apoptotic Cell Death,” Human Molecular Genetics 17, no. 6 (2008): 906–917.

[493] G. K. Tofaris, H. T. Kim, R. Hourez, J. W. Jung, K. P. Kim, and A. L. Goldberg, “Ubiquitin Ligase Nedd4 Promotes Alpha-synuclein Degradation by the Endosomal-lysosomal Pathway,” PNAS 108, no. 41 (2011): 17004–17009.

[494] S. E. Davies, P. J. Hallett, T. Moens, et al., “Enhanced Ubiquitin-dependent Degradation by Nedd4 Protects Against Alpha-synuclein Accumulation and Toxicity in Animal Models of Parkinson's disease,” Neurobiology of Disease 64, no. 100 (2014): 79–87.

[495] M. Kaneko, Y. Okuma, and Y. Nomura, “Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of ,” Journal of Pharmacological Sciences 118, no. 3 (2012): 325–330. Alzheimer's disease.

[496] M. Kaneko, H. Koike, R. Saito, Y. Kitamura, Y. Okuma, and Y. Nomura, “Loss of HRD1-mediated Protein Degradation Causes Amyloid Precursor Protein Accumulation and Amyloid-beta Generation,” Journal of Neuroscience 30, no. 11 (2010): 3924–3932.

[497] Q. Y. Liu, J. X. Lei, M. Sikorska, and R. Liu, “A Novel Brain-enriched E3 Ubiquitin Ligase RNF182 Is Up Regulated in the Brains of Alzheimer's Patients and Targets ATP6V0C for Degradation,” Mol Neurodegener 3 (2008): 4.

[498] N. Sahara, M. Murayama, T. Mizoroki, et al., “In Vivo Evidence of CHIP Up-regulation Attenuating Tau Aggregation,” Journal of Neurochemistry 94, no. 5 (2005): 1254–1263.

[499] C. M. Nadel, A. C. Thwin, M. Callahan, et al., “The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT),” Journal of Molecular Biology 435, no. 11 (2023): 168026.

[500] P. J. Khandelwal, A. M. Herman, H. S. Hoe, G. W. Rebeck, and C. E. Moussa, “Parkin Mediates Beclin-dependent Autophagic Clearance of Defective Mitochondria and Ubiquitinated Abeta in AD Models,” Human Molecular Genetics 20, no. 11 (2011): 2091–2102.

[501] E. M. Rodrigues, S. L. Scudder, M. S. Goo, and G. N. Patrick, “Abeta-Induced Synaptic Alterations Require the E3 Ubiquitin Ligase Nedd4-1,” Journal of Neuroscience 36, no. 5 (2016): 1590–1595.

[502] J. Xu, T. Yu, E. C. Pietronigro, et al., “Peli1 impairs Microglial Aβ Phagocytosis Through Promoting C/EBPβ Degradation,” Plos Biology 18, no. 10 (2020): e3000837.

[503] Y. Liu, Y. Meng, C. Zhou, J. Yan, C. Guo, and W. Dong, “Activation of the IL-17/TRAF6/NF-kappaB Pathway Is Implicated in Abeta-induced Neurotoxicity,” BMC Neuroscience [Electronic Resource] 24, no. 1 (2023): 14.

[504] M. Maheshwari, S. Shekhar, B. K. Singh, et al., “Deficiency of Ube3a in Huntington's Disease Mice Brain Increases Aggregate Load and Accelerates Disease Pathology,” Human Molecular Genetics 23, no. 23 (2014): 6235–6245.

[505] L. Lin, Z. Jin, H. Tan, Q. Xu, T. Peng, and H. Li, “Atypical Ubiquitination by E3 Ligase WWP1 Inhibits the Proteasome-mediated Degradation of Mutant Huntingtin,” Brain Research 1643 (2016): 103–112.

[506] S. Zucchelli, F. Marcuzzi, M. Codrich, et al., “Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Associates With Huntingtin Protein and Promotes Its atypical Ubiquitination to Enhance Aggregate Formation,” Journal of Biological Chemistry 286, no. 28 (2011): 25108–25117.

[507] S. Koyuncu, I. Saez, H. J. Lee, et al., “The Ubiquitin Ligase UBR5 Suppresses Proteostasis Collapse in Pluripotent Stem Cells From Huntington's disease Patients,” Nature Communications 9, no. 1 (2018): 2886.

[508] E. L. Morozko, C. Smith-Geater, A. M. Monteys, et al., “PIAS1 modulates Striatal Transcription, DNA Damage Repair, and SUMOylation With Relevance to Huntington's Disease,” PNAS 118, no. 4 (2021): e2021836118.

[509] W. Poewe, K. Seppi, C. M. Tanner, et al., “Parkinson Disease,” Nature reviews Disease primers 3 (2017): 17013.

[510] M. M. McGregor and A. B. Nelson, “Circuit Mechanisms of Parkinson's Disease,” Neuron 101, no. 6 (2019): 1042–1056.

[511] A. Picca, F. Guerra, R. Calvani, et al., “Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson's Disease: Roads to Biomarker Discovery,” Biomolecules 11, no. 10 (2021): 1508.

[512] S. Geisler, K. M. Holmström, A. Treis, et al., “The PINK1/Parkin-mediated Mitophagy Is Compromised by PD-associated Mutations,” Autophagy 6, no. 7 (2010): 871–878.

[513] F. Kraus, E. A. Goodall, I. R. Smith, et al., “PARK15/FBXO7 is Dispensable for PINK1/Parkin Mitophagy in iNeurons and HeLa Cell Systems,” Embo Reports 24, no. 8 (2023): e56399.

[514] P. M. J. Quinn, P. I. Moreira, A. F. Ambrosio, and C. H. Alves, “PINK1/PARKIN Signalling in Neurodegeneration and Neuroinflammation,” Acta Neuropathol Commun 8, no. 1 (2020): 189.

[515] N. Panicker, V. L. Dawson, and T. M. Dawson, “Activation Mechanisms of the E3 Ubiquitin Ligase Parkin,” Biochemical Journal 474, no. 18 (2017): 3075–3086.

[516] E. H. Clark, A. Vazquez de la Torre, T. Hoshikawa, and T. Briston, “Targeting Mitophagy in Parkinson's Disease,” Journal of Biological Chemistry 296 (2021): 100209.

[517] M. A. Eldeeb, A. N. Bayne, A. Fallahi, et al., “Tom20 gates PINK1 Activity and Mediates Its Tethering of the TOM and TIM23 Translocases Upon Mitochondrial Stress,” PNAS 121, no. 10 (2024): e2313540121.

[518] K. F. Winklhofer, “Parkin and Mitochondrial Quality Control: Toward Assembling the Puzzle,” Trends in Cell Biology 24, no. 6 (2014): 332–341.

[519] S. K. Kalia, S. Lee, P. D. Smith, et al., “BAG5 inhibits Parkin and Enhances Dopaminergic Neuron Degeneration,” Neuron 44, no. 6 (2004): 931–945.

[520] F. Wauters, T. Cornelissen, D. Imberechts, et al., “LRRK2 mutations Impair Depolarization-induced Mitophagy Through Inhibition of Mitochondrial Accumulation of RAB10,” Autophagy 16, no. 2 (2020): 203–222.

[521] K. Y. Ma, M. R. Fokkens, F. Reggiori, M. Mari, and D. S. Verbeek, “Parkinson's Disease-associated VPS35 Mutant Reduces Mitochondrial Membrane Potential and Impairs PINK1/Parkin-mediated Mitophagy,” Transl Neurodegener 10, no. 1 (2021): 19.

[522] E. Im and K. C. Chung, “Dyrk1A phosphorylates Parkin at Ser-131 and Negatively Regulates Its Ubiquitin E3 Ligase Activity,” Journal of Neurochemistry 134, no. 4 (2015): 756–768.

[523] K. K. Chung, B. Thomas, X. Li, et al., “S-nitrosylation of parkin Regulates Ubiquitination and Compromises parkin's Protective Function,” Science 304, no. 5675 (2004): 1328–1331.

[524] M. Funayama, Y. Li, H. Tomiyama, et al., “Leucine-rich Repeat Kinase 2 G2385R Variant Is a Risk Factor for Parkinson Disease in Asian Population,” Neuroreport 18, no. 3 (2007): 273–275.

[525] I. N. Rudenko, A. Kaganovich, D. N. Hauser, et al., “The G2385R Variant of Leucine-rich Repeat Kinase 2 Associated With Parkinson's Disease Is a Partial Loss-of-function Mutation,” Biochemical Journal 446, no. 1 (2012): 99–111.

[526] I. N. Rudenko, A. Kaganovich, R. G. Langston, et al., “The G2385R Risk Factor for Parkinson's Disease Enhances CHIP-dependent Intracellular Degradation of LRRK2,” Biochemical Journal 474, no. 9 (2017): 1547–1558.

[527] E. Liani, A. Eyal, and E. Avraham, “Ubiquitylation of Synphilin-1 and Alpha-synuclein by SIAH and Its Presence in Cellular Inclusions and Lewy Bodies Imply a Role in Parkinson's Disease,” PNAS 101, no. 15 (2004): 5500–5505.

[528] Y. Zhao, M. Lin, F. Zhai, J. Chen, and X. Jin, “Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson's Disease,” Pharmaceuticals (Basel) 17, no. 6 (2024): 782.

[529] D. S. Knopman, H. Amieva, R. C. Petersen, et al., “Alzheimer Disease,” Nature reviews Disease primers 7, no. 1 (2021): 33.

[530] R. K. Moghadam, A. Daraei, M. Haddadi, A. Mardi, N. Karamali, and A. Rezaiemanesh, “Casting Light on the Janus-Faced HMG-CoA Reductase Degradation Protein 1: A Comprehensive Review of Its Dualistic Impact on Apoptosis in Various Diseases,” Molecular Neurobiology 61, no. 9 (2024): 6842–6863.

[531] P. G. Needham, C. J. Guerriero, and J. L. Brodsky, “Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases,” Cold Spring Harbor perspectives in biology 11, no. 8 (2019): a033928.

[532] A. I. Placido, C. R. Oliveira, P. I. Moreira, and C. M. Pereira, “Enhanced Amyloidogenic Processing of Amyloid Precursor Protein and Cell Death Under Prolonged Endoplasmic Reticulum Stress in Brain Endothelial Cells,” Molecular Neurobiology 51, no. 2 (2015): 571–590.

[533] T. Y. Zhou, R. X. Ma, J. Li, et al., “Review of PINK1-Parkin-mediated Mitochondrial Autophagy in Alzheimer's Disease,” European Journal of Pharmacology 959 (2023): 176057.

[534] S. Meftah and J. Gan, “Alzheimer's disease as a Synaptopathy: Evidence for Dysfunction of Synapses During Disease Progression,” Front Synaptic Neurosci 15 (2023): 1129036.

[535] C. Li, Y. Yan, O. Stork, R. Shen, and T. Behnisch, “The E3 Ubiquitin Ligase PRAJA1: A Key Regulator of Synaptic Dynamics and Memory Processes With Implications for Alzheimer's Disease,” International Journal of Molecular Sciences 26, no. 7 (2025): 2909.

[536] Kaur, V. Sharma, and R. Deshmukh, “Activation of Microglia and Astrocytes: A Roadway to Neuroinflammation and Alzheimer's Disease,” Inflammopharmacology 27, no. 4 (2019): 663–677.

[537] W. Wang, Y. Wang, F. Wang, et al., “Gastrodin Regulates the TLR4/TRAF6/NF-kappaB Pathway to Reduce Neuroinflammation and Microglial Activation in an AD Model,” Phytomedicine 128 (2024): 155518.

[538] X. Y. Zhang, J. H. Zhang, X. C. Li, H. Lu, and T. C. Liu, “Exercise-induced Upregulation of TRIM9 Attenuates Neuroinflammation in Alzheimer's Disease-Like Rat,” International Immunopharmacology 144 (2025): 113676.

[539] S. C. Warby, A. Montpetit, A. R. Hayden, et al., “CAG Expansion in the Huntington Disease Gene Is Associated With a Specific and Targetable Predisposing Haplogroup,” American Journal of Human Genetics 84, no. 3 (2009): 351–366.

[540] T. B. Stoker, S. L. Mason, J. C. Greenland, S. T. Holden, H. Santini, and R. A. Barker, “Huntington's Disease: Diagnosis and Management,” Pract Neurol 22, no. 1 (2022): 32–41.

[541] G. B. Landwehrmeyer, S. M. McNeil, D. LSt, et al., “Huntington's Disease Gene: Regional and Cellular Expression in Brain of Normal and Affected Individuals,” Annals of Neurology 37, no. 2 (1995): 218–230.

[542] S. J. Tabrizi, M. D. Flower, C. A. Ross, and E. J. Wild, “Huntington Disease: New Insights Into Molecular Pathogenesis and Therapeutic Opportunities,” Nature reviews Neurology 16, no. 10 (2020): 529–546.

[543] K. P. Bhat, S. Yan, C. E. Wang, S. Li, and X. J. Li, “Differential Ubiquitination and Degradation of Huntingtin Fragments Modulated by Ubiquitin-protein Ligase E3A,” PNAS 111, no. 15 (2014): 5706–5711.

[544] M. Maheshwari, A. Samanta, S. K. Godavarthi, R. Mukherjee, and N. R. Jana, “Dysfunction of the Ubiquitin Ligase Ube3a May be Associated With Synaptic Pathophysiology in a Mouse Model of Huntington Disease,” Journal of Biological Chemistry 287, no. 35 (2012): 29949–29957.

[545] T. Zhao, Y. Hong, P. Yin, S. Li, and X. J. Li, “Differential HspBP1 Expression Accounts for the Greater Vulnerability of Neurons Than Astrocytes to Misfolded Proteins,” PNAS 114, no. 37 (2017): E7803–E7811.

[546] F. Liu, J. Chen, K. Li, et al., “Ubiquitination and Deubiquitination in Cancer: From Mechanisms to Novel Therapeutic Approaches,” Molecular cancer 23, no. 1 (2024): 148.

[547] J. Park, J. Cho, and E. J. Song, “Ubiquitin-proteasome System (UPS) as a Target for Anticancer Treatment,” Arch Pharm Res 43, no. 11 (2020): 1144–1161.

[548] J. Hu, E. Van Valckenborgh, D. Xu, et al., “Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-activated Prodrug TH-302, in Vivo and in Vitro,” Molecular Cancer Therapeutics 12, no. 9 (2013): 1763–1773.

[549] F. Bernassola, M. Karin, A. Ciechanover, and G. Melino, “The HECT family of E3 Ubiquitin Ligases: Multiple Players in Cancer Development,” Cancer Cell 14, no. 1 (2008): 10–21.

[550] K. Inoue, E. A. Fry, and D. P. Frazier, “Transcription Factors That Interact With p53 and Mdm2,” International Journal of Cancer 138, no. 7 (2016): 1577–1585.

[551] U. M. Moll and O. Petrenko, “The MDM2-p53 Interaction,” Molecular Cancer Research 1, no. 14 (2003): 1001–1008.

[552] L. T. Vassilev, “Small-molecule Antagonists of p53-MDM2 Binding: Research Tools and Potential Therapeutics,” Cell Cycle 3, no. 4 (2004): 419–421.

[553] L. T. Vassilev, B. T. Vu, B. Graves, et al., “In Vivo Activation of the p53 Pathway by Small-molecule Antagonists of MDM2,” Science 303, no. 5659 (2004): 844–848.

[554] H. Shen and C. G. Maki, “Pharmacologic Activation of p53 by Small-molecule MDM2 Antagonists,” Current Pharmaceutical Design 17, no. 6 (2011): 560–568.

[555] S. Shangary and S. Wang, “Small-molecule Inhibitors of the MDM2-p53 Protein-protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer Therapy,” Annual Review of Pharmacology and Toxicology 49 (2009): 223–241.

[556] L. Skalniak, J. Kocik, J. Polak, et al., “Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells,” Cancers (Basel) 10, no. 11 (2018): 396.

[557] S. Wang, W. Sun, Y. Zhao, et al., “SAR405838: An Optimized Inhibitor of MDM2-p53 Interaction That Induces Complete and Durable Tumor Regression,” Cancer Research 74, no. 20 (2014): 5855–5865.

[558] T. Unger, T. Juven-Gershon, E. Moallem, et al., “Critical Role for Ser20 of human p53 in the Negative Regulation of p53 by Mdm2,” Embo Journal 18, no. 7 (1999): 1805–1814.

[559] C. Chao, S. Saito, C. W. Anderson, E. Appella, and Y. Xu, “Phosphorylation of Murine p53 at Ser-18 Regulates the p53 Responses to DNA Damage,” PNAS 97, no. 22 (2000): 11936–11941.

[560] C. T. Brew, I. Aronchik, J. C. Hsu, et al., “Indole-3-carbinol Activates the ATM Signaling Pathway Independent of DNA Damage to Stabilize p53 and Induce G1 Arrest of human Mammary Epithelial Cells,” International Journal of Cancer 118, no. 4 (2006): 857–868.

[561] C. Y. Chen, Y. L. Hsu, Y. Y. Chen, J. Y. Hung, M. S. Huang, and P. L. Kuo, “Isokotomolide A, a New Butanolide Extracted From the Leaves of Cinnamomum kotoense, Arrests Cell Cycle Progression and Induces Apoptosis Through the Induction of p53/p21 and the Initiation of Mitochondrial System in human Non-small Cell Lung Cancer A549 Cells,” European Journal of Pharmacology 574, no. 2-3 (2007): 94–102.

[562] D. Spano and G. Catara, “Targeting the Ubiquitin-Proteasome System and Recent Advances in Cancer Therapy,” Cells 13, no. 1 (2023): 29.

[563] X. M. Li, Z. Y. Zhao, X. Yu, et al., “Exploiting E3 Ubiquitin Ligases to Reeducate the Tumor Microenvironment for Cancer Therapy,” Exp Hematol Oncol 12, no. 1 (2023): 34.

[564] A. R. Schneekloth, M. Pucheault, H. S. Tae, and C. M. Crews, “Targeted Intracellular Protein Degradation Induced by a Small Molecule: En Route to Chemical Proteomics,” Bioorganic & medicinal chemistry letters 18, no. 22 (2008): 5904–5908.

[565] T. Yao, H. Xiao, H. Wang, and X. Xu, “Recent Advances in PROTACs for Drug Targeted Protein Research,” International Journal of Molecular Sciences 23, no. 18 (2022): 10328.

[566] D. L. Buckley and C. M. Crews, “Small-molecule Control of Intracellular Protein Levels Through Modulation of the Ubiquitin Proteasome System,” Angewandte Chemie (International ed in English) 53, no. 9 (2014): 2312–2330.

[567] M. S. Gadd, A. Testa, X. Lucas, et al., “Structural Basis of PROTAC Cooperative Recognition for Selective Protein Degradation,” Nature Chemical Biology 13, no. 5 (2017): 514–521.

[568] Z. Liu, M. Hu, Y. Yang, et al., “An Overview of PROTACs: A Promising Drug Discovery Paradigm,” Mol Biomed 3, no. 1 (2022): 46.

[569] X. Li and Y. Song, “Proteolysis-targeting Chimera (PROTAC) for Targeted Protein Degradation and Cancer Therapy,” Journal of hematology & oncology 13, no. 1 (2020): 50.

[570] H. Qian, Y. Zhang, B. Wu, et al., “Structure and Function of HECT E3 Ubiquitin Ligases and Their Role in Oxidative Stress,” J Transl Int Med 8, no. 2 (2020): 71–79.

[571] X. Tian, Y. Chen, Z. Peng, Q. Lin, and A. Sun, “NEDD4 E3 ubiquitin Ligases: Promising Biomarkers and Therapeutic Targets for Cancer,” Biochemical Pharmacology 214 (2023): 115641.

[572] X. Chen, T. Wu, Z. Du, et al., “Discovery of a Brain-permeable Bromodomain and Extra Terminal Domain (BET) Inhibitor With Selectivity for BD1 for the Treatment of Multiple Sclerosis,” European Journal of Medicinal Chemistry 265 (2024): 116080.

[573] D. W. Cescon, J. Hilton, S. Morales Murilo, et al., “A Phase I/II Study of GSK525762 Combined With Fulvestrant in Patients With Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer,” Clinical Cancer Research 30, no. 2 (2024): 334–343.

[574] L. Zhang, B. Riley-Gillis, P. Vijay, and Y. Shen, “Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 Ligase Complexes,” Molecular Cancer Therapeutics 18, no. 7 (2019): 1302–1311.

[575] X. Peng, Z. Hu, L. Zeng, et al., “Overview of Epigenetic Degraders Based on PROTAC, Molecular Glue, and Hydrophobic Tagging Technologies,” Acta Pharm Sin B 14, no. 2 (2024): 533–578.

[576] M. Iconomou and D. N. Saunders, “Systematic Approaches to Identify E3 Ligase Substrates,” Biochemical Journal 473, no. 22 (2016): 4083–4101.

[577] O. Barroso-Gomila, L. Merino-Cacho, V. Muratore, et al., “BioE3 identifies Specific Substrates of Ubiquitin E3 Ligases,” Nature Communications 14, no. 1 (2023): 7656.

[578] H. T. Huang, R. J. Lumpkin, R. W. Tsai, et al., “Ubiquitin-specific Proximity Labeling for the Identification of E3 Ligase Substrates,” Nature Chemical Biology 20, no. 9 (2024): 1227–1236.

[579] M. Watanabe, Y. Saeki, H. Takahashi, et al., “A Substrate-trapping Strategy to Find E3 Ubiquitin Ligase Substrates Identifies Parkin and TRIM28 Targets,” Communications Biology 3, no. 1 (2020): 592.

[580] A. Abbas and F. Ye, “Computational Methods and Key Considerations for in Silico Design of Proteolysis Targeting Chimera (PROTACs),” International Journal of Biological Macromolecules 277, no. Pt 4 (2024): 134293.

[581] Y. Liu, J. Yang, T. Wang, et al., “Expanding PROTACtable Genome Universe of E3 Ligases,” Nature Communications 14, no. 1 (2023): 6509.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.