Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications

Abstract

Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation, and lactylation, differing from traditional acetylation in structure, physicochemical properties, function, and regulation. Aberrant short-chain acyl-PTMs are often associated with tumorigenesis. Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism, drug resistance, and immune responses. This review elucidates the regulatory mechanisms of eight short-chain acyl-PTMs—butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, and lactylation—that are involved in tumor initiation and progression. Their roles in controlling tumor genomic stability, gene transcription, protein stability, enzyme activity, and nuclear localization are summarized, demonstrating their impact on related biological processes such as tumor metabolism, multi-drug resistance, and immune evasion. Additionally, the review provides an overview of current drug research targeting enzymes that regulate PTMs, offering critical insights to advance therapeutic strategies for cancer treatment.

Keywords

cancer / drug resistance / enzyme activity / gene transcription / genomic stability / metabolism / nuclear localization / protein stability / short-chain acyl post-translational modifications

References

[1] Liu J, Qian C, Cao X. Post-Translational Modification Control of Innate Immunity. Immunity. 2016; 45(1): 15-30.

[2] Wu X, Xu M, Geng M, Chen S, Little PJ, Xu S, et al. Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies. Signal Transduct Target Ther. 2023; 8(1): 220.

[3] Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell. 2022; 13(12): 877-919.

[4] Shang S, Liu J, Hua F. Protein acylation: mechanisms, biological functions and therapeutic targets. Signal Transduct Target Ther. 2022; 7(1): 396.

[5] Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M, Žídek A, et al. Highly accurate protein structure prediction for the human proteome. Nature. 2021; 596(7873): 590-6.

[6] Simithy J, Sidoli S, Yuan ZF, Coradin M, Bhanu NV, Marchione DM, et al. Characterization of histone acylations links chromatin modifications with metabolism. Nat Commun. 2017; 8(1): 1141.

[7] Chen Y, Sprung R, Tang Y, Ball H, Sangras B, Kim SC, et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol Cell Proteomics. 2007; 6(5): 812-9.

[8] Zhang Z, Tan M, Xie Z, Dai L, Chen Y, Zhao Y. Identification of lysine succinylation as a new post-translational modification. Nat Chem Biol. 2011; 7(1): 58-63.

[9] Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell. 2011; 146(6): 1016-28.

[10] Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics. 2011; 10(12): M111.012658.

[11] Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 2014; 19(4): 605-17.

[12] Dai L, Peng C, Montellier E, Lu Z, Chen Y, Ishii H, et al. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat Chem Biol. 2014; 10(5): 365-70.

[13] Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, et al. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol Cell. 2016; 62(2): 194-206.

[14] Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019; 574(7779): 575-80.

[15] Zhang D, Tang J, Xu Y, Huang X, Wang Y, Jin X, et al. Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer. Cell Death Dis. 2022; 13(8): 717.

[16] Liao L, He Y, Li SJ, Yu XM, Liu ZC, Liang YY, et al. Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner. Cell Res. 2023; 33(5): 355-71.

[17] Huang H, Wang S, Xia H, Zhao X, Chen K, Jin G, et al. Lactate enhances NMNAT1 lactylation to sustain nuclear NAD(+) salvage pathway and promote survival of pancreatic adenocarcinoma cells under glucose-deprived conditions. Cancer Lett. 2024; 588: 216806.

[18] Sabari BR, Zhang D, Allis CD, Zhao Y. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol. 2017; 18(2): 90-101.

[19] Xu K, Zhang K, Wang Y, Gu Y. Comprehensive review of histone lactylation: Structure, function, and therapeutic targets. Biochem Pharmacol. 2024; 225: 116331.

[20] Figlia G, Willnow P, Teleman AA. Metabolites Regulate Cell Signaling and Growth via Covalent Modification of Proteins. Dev Cell. 2020; 54(2): 156-70.

[21] Kebede AF, Nieborak A, Shahidian LZ, Le Gras S, Richter F, Gómez DA, et al. Histone propionylation is a mark of active chromatin. Nat Struct Mol Biol. 2017; 24(12): 1048-56.

[22] Goudarzi A, Zhang D, Huang H, Barral S, Kwon OK, Qi S, et al. Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters. Mol Cell. 2016; 62(2): 169-80.

[23] Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell. 2013; 50(6): 919-30.

[24] Zhang J, Han ZQ, Wang Y, He QY. Alteration of mitochondrial protein succinylation against cellular oxidative stress in cancer. Mil Med Res. 2022; 9(1): 6.

[25] Sun R, Zhang Z, Bao R, Guo X, Gu Y, Yang W, et al. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. J Hepatol. 2022; 77(2): 453-66.

[26] He H, Hu Z, Xiao H, Zhou F, Yang B. The tale of histone modifications and its role in multiple sclerosis. Hum Genomics. 2018; 12(1): 31.

[27] Yuan H, Wu X, Wu Q, Chatoff A, Megill E, Gao J, et al. Lysine catabolism reprograms tumour immunity through histone crotonylation. Nature. 2023; 617(7962): 818-26.

[28] Zou L, Yang Y, Wang Z, Fu X, He X, Song J, et al. Lysine Malonylation and Its Links to Metabolism and Diseases. Aging Dis. 2023; 14(1): 84-98.

[29] Huang Q, Wu D, Zhao J, Yan Z, Chen L, Guo S, et al. TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. Embo j. 2022; 41(11): e110324.

[30] Bao X, Liu Z, Zhang W, Gladysz K, Fung YME, Tian G, et al. Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics. Mol Cell. 2019; 76(4): 660-75. e9.

[31] Huang H, Tang S, Ji M, Tang Z, Shimada M, Liu X, et al. p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol Cell. 2018; 70(4): 663-78. e6.

[32] Lu Y, Li X, Zhao K, Qiu P, Deng Z, Yao W, et al. Global landscape of 2-hydroxyisobutyrylation in human pancreatic cancer. Front Oncol. 2022; 12: 1001807.

[33] Huang H, Zhang D, Weng Y, Delaney K, Tang Z, Yan C, et al. The regulatory enzymes and protein substrates for the lysine β-hydroxybutyrylation pathway. Sci Adv. 2021; 7(9): eabe2771.

[34] Zhang H, Chang Z, Qin LN, Liang B, Han JX, Qiao KL, et al. MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells. Signal Transduct Target Ther. 2021; 6(1): 135.

[35] Liu Z, Huang Y, Liu X. Lactylation regulated DNA damage repair and cancer cell chemosensitivity. Sci Bull (Beijing). 2024; 69(9): 1185-7.

[36] Li W, Zhou C, Yu L, Hou Z, Liu H, Kong L, et al. Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy. 2024; 20(1): 114-30.

[37] Xiong J, He J, Zhu J, Pan J, Liao W, Ye H, et al. Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell. 2022; 82(9): 1660-77. e10.

[38] Jennings EQ, Fritz KS, Galligan JJ. Biochemical genesis of enzymatic and non-enzymatic post-translational modifications. Mol Aspects Med. 2022; 86: 101053.

[39] Whedon SD, Cole PA. KATs off: Biomedical insights from lysine acetyltransferase inhibitors. Curr Opin Chem Biol. 2023; 72: 102255.

[40] Jin Q, Yu LR, Wang L, Zhang Z, Kasper LH, Lee JE, et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. Embo j. 2011; 30(2): 249-62.

[41] Chen Q, Yang B, Liu X, Zhang XD, Zhang L, Liu T. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Theranostics. 2022; 12(11): 4935-48.

[42] Avvakumov N, Côté J. The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene. 2007; 26(37): 5395-407.

[43] Wolf E, Vassilev A, Makino Y, Sali A, Nakatani Y, Burley SK. Crystal structure of a GCN5-related N-acetyltransferase: Serratia marcescens aminoglycoside 3-N-acetyltransferase. Cell. 1998; 94(4): 439-49.

[44] Xiao HT, Jin J, Zheng ZG. Emerging role of GCN5 in human diseases and its therapeutic potential. Biomed Pharmacother. 2023; 165: 114835.

[45] Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem. 2001; 70: 81-120.

[46] Zhong L, Wu J, Zhou B, Kang J, Wang X, Ye F, et al. ALYREF recruits ELAVL1 to promote colorectal tumorigenesis via facilitating RNA m5C recognition and nuclear export. NPJ Precis Oncol. 2024; 8(1): 243.

[47] Liao P, Bhattarai N, Cao B, Zhou X, Jung JH, Damera K, et al. Crotonylation at serine 46 impairs p53 activity. Biochem Biophys Res Commun. 2020; 524(3): 730-5.

[48] Ma W, Sun Y, Yan R, Zhang P, Shen S, Lu H, et al. OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB. Mol Cell. 2024; 84(3): 538-51. e7.

[49] Zong Z, Xie F, Wang S, Wu X, Zhang Z, Yang B, et al. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell. 2024; 187(10): 2375-92. e33.

[50] Ju J, Zhang H, Lin M, Yan Z, An L, Cao Z, et al. The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. J Clin Invest. 2024; 134(10): e174587.

[51] Sun L, Zhang Y, Yang B, Sun S, Zhang P, Luo Z, et al. Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer. Nat Commun. 2023; 14(1): 6523.

[52] Xie B, Zhang M, Li J, Cui J, Zhang P, Liu F, et al. KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis. Proc Natl Acad Sci U S A. 2024; 121(8): e2314128121.

[53] Niu Z, Chen C, Wang S, Lu C, Wu Z, Wang A, et al. HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription. Nat Commun. 2024; 15(1): 3561.

[54] Li Z, Gong T, Wu Q, Zhang Y, Zheng X, Li Y, et al. Lysine lactylation regulates metabolic pathways and biofilm formation in Streptococcus mutans. Sci Signal. 2023; 16(801): eadg1849.

[55] Liu X, Rong F, Tang J, Zhu C, Chen X, Jia S, et al. Repression of p53 function by SIRT5-mediated desuccinylation at Lysine 120 in response to DNA damage. Cell Death Differ. 2022; 29(4): 722-36.

[56] Wang HL, Chen Y, Wang YQ, Tao EW, Tan J, Liu QQ, et al. Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability. Nat Commun. 2022; 13(1): 6121.

[57] Yuan HF, Zhao M, Zhao LN, Yun HL, Yang G, Geng Y, et al. PRMT5 confers lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours. Acta Pharmacol Sin. 2022; 43(9): 2373-85.

[58] Song X, Yang F, Liu X, Xia P, Yin W, Wang Z, et al. Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis. Nat Chem Biol. 2021; 17(12): 1314-23.

[59] Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, et al. Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability. Genes (Basel). 2020; 11(5): 556.

[60] Sultana F, Manasa KL, Shaik SP, Bonam SR, Kamal A. Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update. Curr Med Chem. 2019; 26(40): 7212-80.

[61] Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature. 1999; 401(6749): 188-93.

[62] Ficner R. Novel structural insights into class I and II histone deacetylases. Curr Top Med Chem. 2009; 9(3): 235-40.

[63] Manal M, Chandrasekar MJ, Gomathi Priya J, Nanjan MJ. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorg Chem. 2016; 67: 18-42.

[64] Sauve AA, Youn DY. Sirtuins: NAD(+)-dependent deacetylase mechanism and regulation. Curr Opin Chem Biol. 2012; 16(5-6): 535-43.

[65] Huang J, Luo Z, Ying W, Cao Q, Huang H, Dong J, et al. 2-Hydroxyisobutyrylation on histone H4K8 is regulated by glucose homeostasis in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2017; 114(33): 8782-7.

[66] Dong H, Zhai G, Chen C, Bai X, Tian S, Hu D, et al. Protein lysine de-2-hydroxyisobutyrylation by CobB in prokaryotes. Sci Adv. 2019; 5(7): eaaw6703.

[67] Andrews FH, Strahl BD, Kutateladze TG. Insights into newly discovered marks and readers of epigenetic information. Nat Chem Biol. 2016; 12(9): 662-8.

[68] Fu Y, Yu J, Li F, Ge S. Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification. J Exp Clin Cancer Res. 2022; 41(1): 144.

[69] Chen C, Chen C, Wang A, Jiang Z, Zhao F, Li Y, et al. ENL reads histone β-hydroxybutyrylation to modulate gene transcription. Nucleic Acids Res. 2024; 52(17): 10029-39.

[70] Hu X, Huang X, Yang Y, Sun Y, Zhao Y, Zhang Z, et al. Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader. Nucleic Acids Res. 2024; 52(10): 5529-48.

[71] Zhai G, Niu Z, Jiang Z, Zhao F, Wang S, Chen C, et al. DPF2 reads histone lactylation to drive transcription and tumorigenesis. Proc Natl Acad Sci U S A. 2024; 121(50): e2421496121.

[72] Flynn EM, Huang OW, Poy F, Oppikofer M, Bellon SF, Tang Y, et al. A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications. Structure. 2015; 23(10): 1801-14.

[73] Xue Q, Yang Y, Li H, Li X, Zou L, Li T, et al. Functions and mechanisms of protein lysine butyrylation (Kbu): Therapeutic implications in human diseases. Genes Dis. 2023; 10(6): 2479-90.

[74] Wang Y, Jin J, Chung MWH, Feng L, Sun H, Hao Q. Identification of the YEATS domain of GAS41 as a pH-dependent reader of histone succinylation. Proc Natl Acad Sci U S A. 2018; 115(10): 2365-70.

[75] Li Y, Sabari BR, Panchenko T, Wen H, Zhao D, Guan H, et al. Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Mol Cell. 2016; 62(2): 181-93.

[76] Zhao D, Guan H, Zhao S, Mi W, Wen H, Li Y, et al. YEATS2 is a selective histone crotonylation reader. Cell Res. 2016; 26(5): 629-32.

[77] Zhang Q, Zeng L, Zhao C, Ju Y, Konuma T, Zhou MM. Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure. 2016; 24(9): 1606-12.

[78] Andrews FH, Shinsky SA, Shanle EK, Bridgers JB, Gest A, Tsun IK, et al. The Taf14 YEATS domain is a reader of histone crotonylation. Nat Chem Biol. 2016; 12(6): 396-8.

[79] Xiong X, Panchenko T, Yang S, Zhao S, Yan P, Zhang W, et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol. 2016; 12(12): 1111-8.

[80] Kabra A, Bushweller J. The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer. J Mol Biol. 2022; 434(1): 167117.

[81] Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022; 12(1): 31-46.

[82] Tubbs A, Nussenzweig A. Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell. 2017; 168(4): 644-56.

[83] Zhao Y, Hao S, Wu W, Li Y, Hou K, Liu Y, et al. Lysine Crotonylation: An Emerging Player in DNA Damage Response. Biomolecules. 2022; 12(10): 1428.

[84] Li L, Shi L, Yang S, Yan R, Zhang D, Yang J, et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat Commun. 2016; 7: 12235.

[85] Hao S, Wang Y, Zhao Y, Gao W, Cui W, Li Y, et al. Dynamic switching of crotonylation to ubiquitination of H2A at lysine 119 attenuates transcription-replication conflicts caused by replication stress. Nucleic Acids Res. 2022; 50(17): 9873-92.

[86] Abu-Zhayia ER, Bishara LA, Machour FE, Barisaac AS, Ben-Oz BM, Ayoub N. CDYL1-dependent decrease in lysine crotonylation at DNA double-strand break sites functionally uncouples transcriptional silencing and repair. Mol Cell. 2022; 82(10): 1940-55. e7.

[87] Abu-Zhayia ER, Awwad SW, Ben-Oz BM, Khoury-Haddad H, Ayoub N. CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair. J Mol Cell Biol. 2018; 10(4): 341-57.

[88] Liao M, Chu W, Sun X, Zheng W, Gao S, Li D, et al. Reduction of H3K27cr Modification During DNA Damage in Colon Cancer. Front Oncol. 2022; 12: 924061.

[89] Han Y, Zhao H, Li G, Jia J, Guo H, Tan J, et al. GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity. Br J Cancer. 2024; 130(10): 1621-34.

[90] Chen Y, Wu J, Zhai L, Zhang T, Yin H, Gao H, et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell. 2024; 187(2): 294-311. e21.

[91] Chen H, Li Y, Li H, Chen X, Fu H, Mao D, et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024; 631(8021): 663-9.

[92] Craig AJ, Silveira MAD, Ma L, Revsine M, Wang L, Heinrich S, et al. Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing. Cell Rep. 2023; 42(11): 113446.

[93] Ji Y, Liu S, Zhang Y, Min Y, Wei L, Guan C, et al. Lysine crotonylation in disease: mechanisms, biological functions and therapeutic targets. Epigenetics Chromatin. 2025; 18(1): 13.

[94] Zhou J, Yan X, Liu Y, Yang J. Succinylation of CTBP1 mediated by KAT2A suppresses its inhibitory activity on the transcription of CDH1 to promote the progression of prostate cancer. Biochem Biophys Res Commun. 2023; 650: 9-16.

[95] Qu M, Long Y, Wang Y, Yin N, Zhang X, Zhang J. Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner. Int J Mol Sci. 2023; 24(8): 7031.

[96] Liao M, Sun X, Zheng W, Wu M, Wang Y, Yao J, et al. LINC00922 decoys SIRT3 to facilitate the metastasis of colorectal cancer through up-regulation the H3K27 crotonylation of ETS1 promoter. Mol Cancer. 2023; 22(1): 163.

[97] Liu N, Konuma T, Sharma R, Wang D, Zhao N, Cao L, et al. Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin. Mol Cell. 2023; 83(13): 2206-21. e11.

[98] De Leo A, Ugolini A, Yu X, Scirocchi F, Scocozza D, Peixoto B, et al. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity. 2024; 57(5): 1105-23. e8.

[99] Yue Q, Wang Z, Shen Y, Lan Y, Zhong X, Luo X, et al. Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention. Adv Sci (Weinh). 2024; 11(19): e2309290.

[100] Xu H, Li L, Wang S, Wang Z, Qu L, Wang C, et al. Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Phytomedicine. 2023; 118: 154940.

[101] Pan L, Feng F, Wu J, Fan S, Han J, Wang S, et al. Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells. Pharmacol Res. 2022; 181: 106270.

[102] Li F, Zhang H, Huang Y, Li D, Zheng Z, Xie K, et al. Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer. Drug Resist Updat. 2024; 73: 101059.

[103] Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, et al. Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021; 22(1): 85.

[104] Yu Y, Huang X, Liang C, Zhang P. Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer. Eur J Pharmacol. 2023; 957: 176007.

[105] Pandkar MR, Sinha S, Samaiya A, Shukla S. Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression. Transl Oncol. 2023; 37: 101758.

[106] Xie B, Lin J, Chen X, Zhou X, Zhang Y, Fan M, et al. CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer. Mol Cancer. 2023; 22(1): 151.

[107] Sun T, Liu B, Li Y, Wu J, Cao Y, Yang S, et al. Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation. J Exp Clin Cancer Res. 2023; 42(1): 253.

[108] Ye J, Gao X, Huang X, Huang S, Zeng D, Luo W, et al. Integrating Single-Cell and Spatial Transcriptomics to Uncover and Elucidate GP73-Mediated Pro-Angiogenic Regulatory Networks in Hepatocellular Carcinoma. Research (Wash D C). 2024; 7: 0387.

[109] Chen B, Deng Y, Hong Y, Fan L, Zhai X, Hu H, et al. Metabolic Recoding of NSUN2-Mediated m(5)C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m(5)C-ENO1 Positive Feedback Loop. Adv Sci (Weinh). 2024; 11(28): e2309840.

[110] Hou X, Ouyang J, Tang L, Wu P, Deng X, Yan Q, et al. KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation. PLoS Biol. 2024; 22(6): e3002666.

[111] Liu M, Gu L, Zhang Y, Li Y, Zhang L, Xin Y, et al. LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma. Cancer Lett. 2024; 595: 217025.

[112] Sun X, He L, Liu H, Thorne RF, Zeng T, Liu L, et al. The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity. Cell Metab. 2023; 35(9): 1563-79. e8.

[113] Duan W, Liu W, Xia S, Zhou Y, Tang M, Xu M, et al. Warburg effect enhanced by AKR1B10 promotes acquired resistance to pemetrexed in lung cancer-derived brain metastasis. J Transl Med. 2023; 21(1): 547.

[114] Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature. 2017; 552(7684): 273-7.

[115] Wang Y, Guo YR, Xing D, Tao YJ, Lu Z. Supramolecular assembly of KAT2A with succinyl-CoA for histone succinylation. Cell Discov. 2018; 4: 47.

[116] Tong Y, Guo D, Yan D, Ma C, Shao F, Wang Y, et al. KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells. Cancer Lett. 2020; 469: 1-10.

[117] Yang G, Yuan Y, Yuan H, Wang J, Yun H, Geng Y, et al. Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis. EMBO Rep. 2021; 22(2): e50967.

[118] Zorro Shahidian L, Haas M, Le Gras S, Nitsch S, Mourão A, Geerlof A, et al. Succinylation of H3K122 destabilizes nucleosomes and enhances transcription. EMBO Rep. 2021; 22(3): e51009.

[119] Liang R, Tan H, Jin H, Wang J, Tang Z, Lu X. The tumour-promoting role of protein homeostasis: Implications for cancer immunotherapy. Cancer Lett. 2023; 573: 216354.

[120] Chen M, Cen K, Song Y, Zhang X, Liou YC, Liu P, et al. NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma. Cancer Lett. 2023; 567: 216285.

[121] Zhu Y, Wang Y, Li Y, Li Z, Kong W, Zhao X, et al. Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer. Commun Biol. 2023; 6(1): 618.

[122] Zhang Z, Wang Y, Liang Z, Meng Z, Zhang X, Ma G, et al. Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression. iScience. 2023; 26(11): 108142.

[123] Meng Q, Sun H, Zhang Y, Yang X, Hao S, Liu B, et al. Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression. J Exp Clin Cancer Res. 2024; 43(1): 36.

[124] Wang C, Zhang C, Li X, Shen J, Xu Y, Shi H, et al. CPT1A-mediated succinylation of S100A10 increases human gastric cancer invasion. J Cell Mol Med. 2019; 23(1): 293-305.

[125] Wang X, Shi X, Lu H, Zhang C, Li X, Zhang T, et al. Succinylation Inhibits the Enzymatic Hydrolysis of the Extracellular Matrix Protein Fibrillin 1 and Promotes Gastric Cancer Progression. Adv Sci (Weinh). 2022; 9(27): e2200546.

[126] Yang S, Zhan Q, Su D, Cui X, Zhao J, Wang Q, et al. HIF1α/ATF3 partake in PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma. Neuro Oncol. 2024; 26(8): 1405-20.

[127] Jiang M, Huang Z, Chen L, Deng T, Liu J, Wu Y. SIRT5 promote malignant advancement of chordoma by regulating the desuccinylation of c-myc. BMC Cancer. 2024; 24(1): 386.

[128] He Y, Zheng CC, Yang J, Li SJ, Xu TY, Wei X, et al. Lysine butyrylation of HSP90 regulated by KAT8 and HDAC11 confers chemoresistance. Cell Discov. 2023; 9(1): 74.

[129] Hou JY, Cao J, Gao LJ, Zhang FP, Shen J, Zhou L, et al. Upregulation of α enolase (ENO1) crotonylation in colorectal cancer and its promoting effect on cancer cell metastasis. Biochem Biophys Res Commun. 2021; 578: 77-83.

[130] Zhang XY, Liu ZX, Zhang YF, Xu LX, Chen MK, Zhou YF, et al. SEPT2 crotonylation promotes metastasis and recurrence in hepatocellular carcinoma and is associated with poor survival. Cell Biosci. 2023; 13(1): 63.

[131] Zheng Y, Zhu L, Qin ZY, Guo Y, Wang S, Xue M, et al. Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression. Cell Rep. 2023; 42(7): 112666.

[132] Huang H, Luo Z, Qi S, Huang J, Xu P, Wang X, et al. Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway. Cell Res. 2018; 28(1): 111-25.

[133] Jia M, Yue X, Sun W, Zhou Q, Chang C, Gong W, et al. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Sci Adv. 2023; 9(22): eadg4993.

[134] Sun W, Jia M, Feng Y, Cheng X. Lactate is a bridge linking glycolysis and autophagy through lactylation. Autophagy. 2023; 19(12): 3240-1.

[135] Yang Z, Yan C, Ma J, Peng P, Ren X, Cai S, et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab. 2023; 5(1): 61-79.

[136] Meng Q, Zhang Y, Sun H, Yang X, Hao S, Liu B, et al. Human papillomavirus-16 E6 activates the pentose phosphate pathway to promote cervical cancer cell proliferation by inhibiting G6PD lactylation. Redox Biol. 2024; 71: 103108.

[137] Wang YF, Zhao LN, Geng Y, Yuan HF, Hou CY, Zhang HH, et al. Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer. Acta Pharmacol Sin. 2023; 44(1): 211-20.

[138] Kwon OK, Bang IH, Choi SY, Jeon JM, Na AY, Gao Y, et al. LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer. Genomics Proteomics Bioinformatics. 2023; 21(1): 177-89.

[139] Teng P, Cui K, Yao S, Fei B, Ling F, Li C, et al. SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration. Cell Death Differ. 2024; 31(1): 65-77.

[140] Yang X, Wang Z, Li X, Liu B, Liu M, Liu L, et al. SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation. Cancer Res. 2018; 78(2): 372-86.

[141] Yihan L, Xiaojing W, Ao L, Chuanjie Z, Haofei W, Yan S, et al. SIRT5 functions as a tumor suppressor in renal cell carcinoma by reversing the Warburg effect. J Transl Med. 2021; 19(1): 521.

[142] Shi L, Duan R, Sun Z, Jia Q, Wu W, Wang F, et al. LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer. Cell Death Differ. 2023; 30(6): 1517-32.

[143] Hou JY, Gao LJ, Shen J, Zhou L, Shi JY, Sun T, et al. Crotonylation of PRKACA enhances PKA activity and promotes colorectal cancer development via the PKA-FAK-AKT pathway. Genes Dis. 2023; 10(2): 332-5.

[144] Yu Z, Peng Y, Gao J, Zhou M, Shi L, Zhao F, et al. The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis. Sci Adv. 2023; 9(26): eade0387.

[145] Dong Y, Hu H, Zhang X, Zhang Y, Sun X, Wang H, et al. Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis. Signal Transduct Target Ther. 2023; 8(1): 95.

[146] Guo Z, Pan F, Peng L, Tian S, Jiao J, Liao L, et al. Systematic Proteome and Lysine Succinylome Analysis Reveals Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Carcinoma. Mol Cell Proteomics. 2021; 20: 100053.

[147] Liu K, Li F, Sun Q, Lin N, Han H, You K, et al. p53 β-hydroxybutyrylation attenuates p53 activity. Cell Death Dis. 2019; 10(3): 243.

[148] Gaddameedi JD, Chou T, Geller BS, Rangarajan A, Swaminathan TA, Dixon D, et al. Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1). J Med Chem. 2023; 66(8): 5774-801.

[149] Abbineni C, Thiyagarajan S, Senaiar RS, Mukherjee S, Jaleel M, Marappan S, et al. Abstract 1143: Evaluation of AU-18069, a novel small molecule CBP/p300 bromodomain inhibitor for the treatment of cancers. Cancer Res. 2021; 81(13_Supplement): 1143.

[150] Yang Y, Zhang R, Li Z, Mei L, Wan S, Ding H, et al. Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors. J Med Chem. 2020; 63(3): 1337-60.

[151] Kanada R, Kagoshima Y, Asano M, Suzuki T, Murata T, Haruta M, et al. Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring. Bioorg Med Chem Lett. 2022; 66: 128726.

[152] Popp TA, Tallant C, Rogers C, Fedorov O, Brennan PE, Müller S, et al. Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors. J Med Chem. 2016; 59(19): 8889-912.

[153] van Gils N, Martiañez Canales T, Vermue E, Rutten A, Denkers F, van der Deure T, et al. The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells. Hemasphere. 2021; 5(8): e610.

[154] Jung M, Nicholas N, Grindrod S, Dritschilo A. Dual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth. PLoS One. 2024; 19(7): e0306168.

[155] Mahmud I, Tian G, Wang J, Stowe R, Huo Z, Zhang Y, et al. Abstract 4718: SR-4370, a potent and selective inhibitor of class I HDACs, suppresses AR signaling and in vivo prostate tumor growth. Cancer Res. 2019; 79(13_Supplement): 4718.

[156] Luckhurst CA, Aziz O, Beaumont V, Bürli RW, Breccia P, Maillard MC, et al. Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. Bioorg Med Chem Lett. 2019; 29(1): 83-8.

[157] Turkman N, Liu D, Pirola I. Design, synthesis, biochemical evaluation, radiolabeling and in vivo imaging with high affinity class-IIa histone deacetylase inhibitor for molecular imaging and targeted therapy. Eur J Med Chem. 2022; 228: 114011.

[158] Itoh Y, Zhan P, Tojo T, Jaikhan P, Ota Y, Suzuki M, et al. Discovery of Selective Histone Deacetylase 1 and 2 Inhibitors: Screening of a Focused Library Constructed by Click Chemistry, Kinetic Binding Analysis, and Biological Evaluation. J Med Chem. 2023; 66(22): 15171-88.

[159] Chen J-S, Chou C-H, Wu Y-H, Yang M-H, Chu S-H, Chen Y-F, et al. Preclinical development of GNTbm-38, a novel class I histone deacetylase inhibitor, while combined with anti-VEGFR TKI or anti-PD-1 Ab: Assessment of immune activation and immune memory in cancer immunotherapy. J Clin Oncol. 2025; 43(16_suppl): 2574.

[160] Wang T, Gonzales P, Kotlarczyk K, Lee M-J, Bossert E, Devore C, et al. Abstract LB-058: GB-3103, an epigenetic immunomodulator, shows potent antitumor activity against tumors harboring dual loss of SMARCA4/SMARCA2 ATPases. Cancer Res. 2019; 79(13_Supplement): LB-058.

[161] Fossati G, Ripamonti C, Caprini G, Pozzi P, Galbiati E, Cordella P, et al. Abstract 1358: The selective HDAC6 inhibitor ITF3756 stimulates an antitumor immune response and leads to tumor regression in combination with anti CTLA-4 antibody in a colon carcinoma murine model. Cancer Res. 2022; 82(12_Supplement): 1358.

[162] Harding RJ, Franzoni I, Mann MK, Szewczyk MM, Mirabi B, Ferreira de Freitas R, et al. Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6. J Med Chem. 2023; 66(15): 10273-88.

[163] Noonepalle SKR, Grindrod S, Aghdam N, Li X, Gracia-Hernandez M, Zevallos-Delgado C, et al. Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition. Mol Cancer Ther. 2023; 22(12): 1376-89.

[164] Olaoye OO, Watson PR, Nawar N, Geletu M, Sedighi A, Bukhari S, et al. Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype. J Med Chem. 2021; 64(5): 2691-704.

[165] Lai Z, Ni H, Hu X, Cui S. Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma. J Med Chem. 2023; 66(15): 10791-807.

[166] Lee SY, Shin H-S, Choi J. Abstract 4458: New HDAC inhibitor (M166) has a synergistic effect with immune checkpoint inhibitor in lung cancer treatment. Cancer Res. 2020; 80(16_Supplement): 4458.

[167] Huang WJ, Liang YC, Chuang SE, Chi LL, Lee CY, Lin CW, et al. NBM-HD-1: A Novel Histone Deacetylase Inhibitor with Anticancer Activity. Evid Based Complement Alternat Med. 2012; 2012: 781417.

[168] Vesci L, Bernasconi E, Milazzo FM, De Santis R, Gaudio E, Kwee I, et al. Preclinical antitumor activity of ST7612AA1: a new oral thiol-based histone deacetylase (HDAC) inhibitor. Oncotarget. 2015; 6(8): 5735-48.

[169] Camero S, Milazzo L, Vulcano F, Pedini F, Pontecorvi P, Gerini G, et al. 105P SFX-01 in the treatment of rhabdomyosarcoma: Preclinical results in cellular models. ESMO Open. 2023; 8(1): 101142.

[170] Wang Y, Zhang J, Li K, Xia S, Gou S. Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit. J Med Chem. 2024; 67(3): 2066-82.

[171] Mensah AA, Valente S, Matkovic M, Sartori G, Falzarano C, Tarantelli C, et al. Abstract 3279: Dual inhibition of EZH2 and histone deacetylases for the treatment of lymphomas with epigenetic aberrations. Cancer Res. 2022; 82(12_Supplement): 3279.

[172] Jin H, Liang L, Liu L, Deng W, Liu J. HDAC inhibitor DWP0016 activates p53 transcription and acetylation to inhibit cell growth in U251 glioblastoma cells. J Cell Biochem. 2013; 114(7): 1498-509.

[173] Ostwal V, Ramaswamy A, Bhargava P, Srinivas S, Mandavkar S, Chaugule D, et al. A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study). Med Oncol. 2022; 40(1): 17.

[174] Wang Y, Wang H, Ge H, Yang Z. AG-1031 induced autophagic cell death and apoptosis in C6 glioma cells associated with Notch-1 signaling pathway. J Cell Biochem. 2018; 119(7): 5893-903.

[175] Hong JY, Jing H, Price IR, Cao J, Bai JJ, Lin H. Simultaneous Inhibition of SIRT2 Deacetylase and Defatty-Acylase Activities via a PROTAC Strategy. ACS Med Chem Lett. 2020; 11(11): 2305-11.

[176] Mellini P, Itoh Y, Tsumoto H, Li Y, Suzuki M, Tokuda N, et al. Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, “selectivity pocket” and NAD(+)-binding site. Chem Sci. 2017; 8(9): 6400-8.

[177] Breen ME, Mapp AK. Modulating the masters: chemical tools to dissect CBP and p300 function. Curr Opin Chem Biol. 2018; 45: 195-203.

[178] Welti J, Sharp A, Brooks N, Yuan W, McNair C, Chand SN, et al. Targeting the p300/CBP Axis in Lethal Prostate Cancer. Cancer Discov. 2021; 11(5): 1118-37.

[179] Armstrong AJ, Gordon MS, Reimers MA, Sedkov A, Lipford K, Snavely-Merhaut J, et al. The Courage study: A first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer. J Clin Oncol. 2021; 39(15_suppl): TPS5085.

[180] Huang M, Zhang J, Yan C, Li X, Zhang J, Ling R. Small molecule HDAC inhibitors: Promising agents for breast cancer treatment. Bioorg Chem. 2019; 91: 103184.

[181] Park SY, Kim JS. A short guide to histone deacetylases including recent progress on class II enzymes. Exp Mol Med. 2020; 52(2): 204-12.

[182] Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 2007; 25(1): 84-90.

[183] Amengual JE, Lichtenstein R, Lue J, Sawas A, Deng C, Lichtenstein E, et al. A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood. 2018; 131(4): 397-407.

[184] Duvic M, Dummer R, Becker JC, Poulalhon N, Ortiz Romero P, Grazia Bernengo M, et al. Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer. 2013; 49(2): 386-94.

[185] Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol. 2011; 29(15): 2052-9.

[186] Jiang Z, Li W, Hu X, Zhang Q, Sun T, Cui S, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20(6): 806-15.

[187] Connolly RM, Zhao F, Miller KD, Lee MJ, Piekarz RL, Smith KL, et al. E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2021; 39(28): 3171-81.

[188] Gong K, Wang M, Duan Q, Li G, Yong D, Ren C, et al. High-yield production of FK228 and new derivatives in a Burkholderia chassis. Metab Eng. 2023; 75: 131-42.

[189] Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014; 13(9): 673-91.

[190] Zheng X, Liu Z, Zhong J, Zhou L, Chen J, Zheng L, et al. Downregulation of HINFP induces senescence-associated secretory phenotype to promote metastasis in a non-cell-autonomous manner in bladder cancer. Oncogene. 2022; 41(28): 3587-98.

[191] Huang X, Feng Z, Liu D, Gou Y, Chen M, Tang D, et al. PTMD 2.0: an updated database of disease-associated post-translational modifications. Nucleic Acids Res. 2025; 53(D1): D554-D63.

[192] Li Z, Li S, Luo M, Jhong JH, Li W, Yao L, et al. dbPTM in 2022: an updated database for exploring regulatory networks and functional associations of protein post-translational modifications. Nucleic Acids Res. 2022; 50(D1): D471-D9.

[193] Jiang P, Ning W, Shi Y, Liu C, Mo S, Zhou H, et al. FSL-Kla: A few-shot learning-based multi-feature hybrid system for lactylation site prediction. Comput Struct Biotechnol J. 2021; 19: 4497-509.

[194] Dai W, Qiao X, Fang Y, Guo R, Bai P, Liu S, et al. Epigenetics-targeted drugs: current paradigms and future challenges. Signal Transduct Target Ther. 2024; 9(1): 332.

[195] Tong Y, Gao WQ, Liu Y. Metabolic heterogeneity in cancer: An overview and therapeutic implications. Biochim Biophys Acta Rev Cancer. 2020; 1874(2): 188421.

[196] Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther. 2025; 10(1): 38.

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