Wnt Signaling Pathway: Biological Function, Diseases, and Therapeutic Interventions

Abstract

The Wnt signaling pathway deeply participates in multiple physiological and pathological processes. Its activity is intricately regulated by a diverse network of modulators, reflecting the pathway's structural and functional complexity. Dysregulation of Wnt signaling leads to cellular dysfunction and is associated with a wide spectrum of diseases, among which tissue fibrosis represents a major pathological outcome, characterized by activation of myofibroblasts and subsequent excessive deposition of extracellular matrix in response to injury. Wnt signaling is a central driver of fibrotic progression across multiple tissues and organs; however, effective therapeutic strategies directly targeting Wnt signaling in fibrosis remain scarce. In this review, we provide a comprehensive overview of Wnt pathway components, regulatory mechanisms, and therapeutic approaches. We systematically examine how Wnt signaling governs both developmental processes and pathological conditions, with particular emphasis on its role in fibrosis while also extending discussion to other diseases. Special attention is devoted to the secreted frizzled-related proteins (SFRPs) family, soluble regulators with biphasic, context-dependent effects that are especially relevant in fibrosis. Finally, we summarize insights from preclinical and clinical studies, review advances and challenges in the development of small-molecule compounds targeting Wnt components, highlighting the vital role of SFRPs as promising targets for antifibrotic intervention.

Keywords

fibrosis / myofibroblast activation / secreted frizzled-related protein (SFRP) / therapeutic targeting / Wnt signaling

References

[1] R. Nusse and H. Clevers, “Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities,” Cell 169, no. 6 (2017): 985–999.

[2] S.-S. Li, Q. Sun, M.-R. Hua, et al., “Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis,” Frontiers in Pharmacology 12 (2021): 719880.

[3] B. T. MacDonald, K. Tamai, and X. He, “Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases,” Developmental Cell 17, no. 1 (2009): 9–26.

[4] R. Nusse and H. E. Varmus, “Many Tumors Induced by the Mouse Mammary Tumor Virus Contain a Provirus Integrated in the Same Region of the Host Genome,” Cell 31, no. 1 (1982): 99–109.

[5] C. Nusslein-Volhard and E. Wieschaus, “Mutations Affecting Segment Number and Polarity in Drosophila,” Nature 287, no. 5785 (1980): 795–801.

[6] F. Rijsewijk, M. Schuermann, E. Wagenaar, P. Parren, D. Weigel, and R. Nusse, “The Drosophila Homolog of the Mouse Mammary Oncogene Int-1 Is Identical to the Segment Polarity Gene Wingless,” Cell 50, no. 4 (1987): 649–657.

[7] J. Noordermeer, J. Klingensmith, and N. Perrimon, “Nusse R. dishevelled and Armadillo Act in the Wingless Signalling Pathway in Drosophila,” Nature 367, no. 6458 (1994): 80–83.

[8] M. Peifer, D. Sweeton, M. Casey, and E. Wieschaus, “wingless Signal and Zeste-white 3 Kinase Trigger Opposing Changes in the Intracellular Distribution of Armadillo,” Development (Cambridge, England) 120, no. 2 (1994): 369–380.

[9] E. Siegfried and T. B. Chou, “Perrimon N. wingless Signaling Acts Through Zeste-white 3, the Drosophila Homolog of Glycogen Synthase Kinase-3, to Regulate Engrailed and Establish Cell Fate,” Cell 71, no. 7 (1992): 1167–1179.

[10] H. Clevers and R. Nusse, “Wnt/Beta-catenin Signaling and Disease,” Cell 149, no. 6 (2012): 1192–1205.

[11] M. M. Maurice and S. Angers, “Mechanistic Insights Into Wnt-beta-catenin Pathway Activation and Signal Transduction,” Nature Reviews Molecular Cell Biology 26, no. 5 (2025): 371–388.

[12] I. Akoumianakis, M. Polkinghorne, and C. Antoniades, “Non-canonical WNT Signalling in Cardiovascular Disease: Mechanisms and Therapeutic Implications,” Nature Reviews Cardiology 19, no. 12 (2022): 783–797.

[13] R. Hayat, M. Manzoor, and A. Hussain, “Wnt Signaling Pathway: A Comprehensive Review,” Cell Biology International 46, no. 6 (2022): 863–877.

[14] J. Liu, Q. Xiao, J. Xiao, et al., “Wnt/Beta-catenin Signalling: Function, Biological Mechanisms, and Therapeutic Opportunities,” Signal Transduct Target Ther 7, no. 1 (2022): 3.

[15] Z. Steinhart and S. Angers, “Wnt Signaling in Development and Tissue Homeostasis,” Development (Cambridge, England) 145, no. 11 (2018): dev146589.

[16] C. Niehrs, “On Growth and Form: A Cartesian Coordinate System of Wnt and BMP Signaling Specifies Bilaterian Body Axes,” Development (Cambridge, England) 137, no. 6 (2010): 845–857.

[17] J. H. Van Es, P. Jay, A. Gregorieff, et al., “Wnt Signalling Induces Maturation of Paneth Cells in Intestinal Crypts,” Nature Cell Biology 7, no. 4 (2005): 381–386.

[18] H. Clevers, “Wnt/Beta-catenin Signaling in Development and Disease,” Cell 127, no. 3 (2006): 469–480.

[19] J. Huelsken, R. Vogel, B. Erdmann, and G. Cotsarelis, “Birchmeier W. beta-Catenin Controls Hair Follicle Morphogenesis and Stem Cell Differentiation in the Skin,” Cell 105, no. 4 (2001): 533–545.

[20] C. P. Heisenberg, M. Tada, G. J. Rauch, et al., “Silberblick/Wnt11 Mediates Convergent Extension Movements During Zebrafish Gastrulation,” Nature 405, no. 6782 (2000): 76–81.

[21] J. R. K. Seifert and M. Mlodzik, “Frizzled/PCP Signalling: A Conserved Mechanism Regulating Cell Polarity and Directed Motility,” Nature Reviews Genetics 8, no. 2 (2007): 126–138.

[22] Y. Gong, C. Mo, and S. E. Fraser, “Planar Cell Polarity Signalling Controls Cell Division Orientation During Zebrafish Gastrulation,” Nature 430, no. 7000 (2004): 689–693.

[23] M. Kühl, L. C. Sheldahl, M. Park, J. R. Miller, and R. T. Moon, “The Wnt/Ca2+ Pathway: A New Vertebrate Wnt Signaling Pathway Takes Shape,” Trends in Genetics 16, no. 7 (2000): 279–283.

[24] T. Saneyoshi, S. Kume, Y. Amasaki, and K. Mikoshiba, “The Wnt/Calcium Pathway Activates NF-AT and Promotes Ventral Cell Fate in Xenopus Embryos,” Nature 417, no. 6886 (2002): 295–299.

[25] L. Ma and H. Y. Wang, “Suppression of Cyclic GMP-dependent Protein Kinase Is Essential to the Wnt/cGMP/Ca2+ Pathway,” Journal of Biological Chemistry 281, no. 41 (2006): 30990–31001.

[26] N. C. Henderson, F. Rieder, and T. A. Wynn, “Fibrosis: From Mechanisms to Medicines,” Nature 587, no. 7835 (2020): 555–566.

[27] C. Beyer, A. Schramm, A. Akhmetshina, et al., “β-catenin Is a central Mediator of Pro-fibrotic Wnt Signaling in Systemic Sclerosis,” Annals of the Rheumatic Diseases 71, no. 5 (2012): 761–767.

[28] A. P. Lam and C. J. Gottardi, “β-catenin Signaling: A Novel Mediator of Fibrosis and Potential Therapeutic Target,” Current Opinion in Rheumatology 23, no. 6 (2011): 562–567.

[29] T. A. Wynn, “Cellular and Molecular Mechanisms of Fibrosis,” Journal of Pathology 214, no. 2 (2008): 199–210.

[30] M. Pakyari, A. Farrokhi, M. K. Maharlooei, and A. Ghahary, “Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing,” Adv Wound Care (New Rochelle) 2, no. 5 (2013): 215–224.

[31] Y. Kawano and R. Kypta, “Secreted Antagonists of the Wnt Signalling Pathway,” Journal of Cell Science 116 (2003): 2627–2634. Pt 13.

[32] P. Bovolenta, P. Esteve, J. M. Ruiz, E. Cisneros, and J. Lopez-Rios, “Beyond Wnt Inhibition: New Functions of Secreted Frizzled-related Proteins in Development and Disease,” Journal of Cell Science 121 (2008): 737–746. Pt 6.

[33] Y. Y. Cheng, J. Yu, Y. P. Wong, et al., “Frequent Epigenetic Inactivation of Secreted Frizzled-related Protein 2 (SFRP2) by Promoter Methylation in human Gastric Cancer,” British Journal of Cancer 97, no. 7 (2007): 895–901.

[34] A. Uren, F. Reichsman, V. Anest, et al., “Secreted Frizzled-related Protein-1 Binds Directly to Wingless and Is a Biphasic Modulator of Wnt Signaling,” Journal of Biological Chemistry 275, no. 6 (2000): 4374–4382.

[35] Q. Schenkelaars, L. Fierro-Constain, E. Renard, A. L. Hill, and C. Borchiellini, “Insights Into Frizzled Evolution and New Perspectives,” Evolution & Development 17, no. 2 (2015): 160–169.

[36] N. Tsutsumi, S. Mukherjee, D. Waghray, et al., “Structure of human Frizzled5 by Fiducial-assisted Cryo-EM Supports a Heterodimeric Mechanism of Canonical Wnt Signaling,” Elife 9 (2020): e58464.

[37] Y. Yang and M. Mlodzik, “Wnt-Frizzled/Planar Cell Polarity Signaling: Cellular Orientation by Facing the Wind (Wnt),” Annual Review of Cell and Developmental Biology 31 (2015): 623–646.

[38] C. Fuerer, S. J. Habib, and R. Nusse, “A Study on the Interactions Between Heparan Sulfate Proteoglycans and Wnt Proteins,” Developmental Dynamics 239, no. 1 (2010): 184–190.

[39] Y. Zhu and X. Li, “Advances of Wnt Signalling Pathway in Colorectal Cancer,” Cells 12, no. 3 (2023): 447.

[40] J. Neuhaus, A. Weimann, and M. Berndt-Paetz, “Immunocytochemical Analysis of Endogenous Frizzled-(Co-)Receptor Interactions and Rapid Wnt Pathway Activation in Mammalian Cells,” International Journal of Molecular Sciences 22, no. 21 (2021): 12057.

[41] A. D. Kohn and R. T. Moon, “Wnt and Calcium Signaling: β-Catenin-independent Pathways,” Cell Calcium 38, no. 3-4 (2005): 439–446.

[42] Y. Tang, Y. Chen, R. Liu, W. Li, B. Hua, and Y. Bao, “Wnt Signaling Pathways: A Role in Pain Processing,” Neuromolecular Med 24, no. 3 (2022): 233–249.

[43] H. Zhang, H. Zhang, Y. Zhang, et al., “Dishevelled-DEP Domain Interacting Protein (DDIP) Inhibits Wnt Signaling by Promoting TCF4 Degradation and Disrupting the TCF4/Beta-catenin Complex,” Cell Signalling 22, no. 11 (2010): 1753–1760.

[44] A. De, “Wnt/Ca2+ Signaling Pathway: A Brief Overview,” Acta Biochim Biophys Sin (Shanghai) 43, no. 10 (2011): 745–756.

[45] M. M. Ni, Y. R. Wang, W. W. Wu, et al., “Novel Insights on Notch Signaling Pathways in Liver Fibrosis,” European Journal of Pharmacology 826 (2018): 66–74.

[46] M. Huang, A. Chang, M. Choi, D. Zhou, F. A. Anania, and C. H. Shin, “Antagonistic Interaction Between Wnt and Notch Activity Modulates the Regenerative Capacity of a Zebrafish Fibrotic Liver Model,” Hepatology 60, no. 5 (2014): 1753–1766.

[47] M. Edeling, G. Ragi, S. Huang, H. Pavenstädt, and K. Susztak, “Developmental Signalling Pathways in Renal Fibrosis: The Roles of Notch, Wnt and Hedgehog,” Nature Reviews Nephrology 12, no. 7 (2016): 426–439.

[48] S. Zmorzyński, W. Styk, A. A. Filip, and D. Krasowska, “The Significance of NOTCH Pathway in the Development of Fibrosis in Systemic Sclerosis,” Ann Dermatol 31, no. 4 (2019): 365–371.

[49] L. Marquez-Exposito, E. Cantero-Navarro, C. Lavoz, et al., “Could Notch Signaling Pathway be a Potential Therapeutic Option in Renal Diseases?,” Nefrologia (Engl Ed) 38, no. 5 (2018): 466–475.

[50] R. J. Tan, D. Zhou, L. Zhou, and Y. Liu, “Wnt/β-catenin Signaling and Kidney Fibrosis,” Kidney Int Suppl (2011) 4, no. 1 (2014): 84–90.

[51] A. Akhmetshina, K. Palumbo, C. Dees, et al., “Activation of Canonical Wnt Signalling Is Required for TGF-β-mediated Fibrosis,” Nature Communications 3 (2012): 735.

[52] A. Vallée, Y. Lecarpentier, R. Guillevin, and J. N. Vallée, “Interactions Between TGF-β1, Canonical WNT/β-catenin Pathway and PPAR γ in Radiation-induced Fibrosis,” Oncotarget 8, no. 52 (2017): 90579–90604.

[53] F. Yousefi, Z. Shabaninejad, S. Vakili, et al., “TGF-β and WNT Signaling Pathways in Cardiac Fibrosis: Non-coding RNAs Come Into Focus,” Cell Communication and Signaling 18, no. 1 (2020): 87.

[54] P. Cisternas, C. P. Vio, and N. C. Inestrosa, “Role of Wnt Signaling in Tissue Fibrosis, Lessons From Skeletal Muscle and Kidney,” Current Molecular Medicine 14, no. 4 (2014): 510–522.

[55] Z. G. Ma, Y. P. Yuan, H. M. Wu, X. Zhang, and Q. Z. Tang, “Cardiac Fibrosis: New Insights Into the Pathogenesis,” Int J Biol Sci 14, no. 12 (2018): 1645–1657.

[56] Y. Y. Ho, D. Lagares, A. M. Tager, and M. Kapoor, “Fibrosis–a Lethal Component of Systemic Sclerosis,” Nat Rev Rheumatol 10, no. 7 (2014): 390–402.

[57] M. V. Enzo, M. Rastrelli, C. R. Rossi, U. Hladnik, and D. Segat, “The Wnt/β-catenin Pathway in human Fibrotic-Like Diseases and Its Eligibility as a Therapeutic Target,” Mol Cell Ther 3 (2015): 1.

[58] H. J. Zhangdi, S. B. Su, F. Wang, et al., “Crosstalk Network Among Multiple Inflammatory Mediators in Liver Fibrosis,” World Journal of Gastroenterology 25, no. 33 (2019): 4835–4849.

[59] A. Horn, K. Palumbo, C. Cordazzo, et al., “Hedgehog Signaling Controls Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis,” Arthritis and Rheumatism 64, no. 8 (2012): 2724–2733.

[60] N. N. El-Agroudy, R. N. El-Naga, R. A. El-Razeq, and E. El-Demerdash, “Forskolin, a Hedgehog Signalling Inhibitor, Attenuates Carbon Tetrachloride-induced Liver Fibrosis in Rats,” British Journal of Pharmacology 173, no. 22 (2016): 3248–3260.

[61] A. Omenetti, A. Porrello, Y. Jung, et al., “Hedgehog Signaling Regulates Epithelial-mesenchymal Transition During Biliary Fibrosis in Rodents and Humans,” Journal of Clinical Investigation 118, no. 10 (2008): 3331–3342.

[62] W. Qin, L. Cao, and I. Y. Massey, “Role of PI3K/Akt Signaling Pathway in Cardiac Fibrosis,” Molecular and Cellular Biochemistry 476, no. 11 (2021): 4045–4059.

[63] W. D. Hardie, S. W. Glasser, and J. S. Hagood, “Emerging Concepts in the Pathogenesis of Lung Fibrosis,” American Journal of Pathology 175, no. 1 (2009): 3–16.

[64] E. Shamsan, M. Almezgagi, M. Gamah, et al., “The Role of PI3k/AKT Signaling Pathway in Attenuating Liver Fibrosis: A Comprehensive Review,” Front Med (Lausanne) 11 (2024): 1389329.

[65] A. Vallée and Y. Lecarpentier, “Crosstalk between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress during Carcinogenesis,” Frontiers in immunology 9 (2018): 745.

[66] D. V. N. Somanader, P. Zhao, R. E. Widdop, and C. S. Samuel, “The Involvement of the Wnt/β-catenin Signaling Cascade in Fibrosis Progression and Its Therapeutic Targeting by Relaxin,” Biochemical Pharmacology 223 (2024): 116130.

[67] E. Y. Rim, H. Clevers, and R. Nusse, “The Wnt Pathway: From Signaling Mechanisms to Synthetic Modulators,” Annual Review of Biochemistry 91 (2022): 571–598.

[68] S. Annunziato, T. Sun, and J. S. Tchorz, “The RSPO-LGR4/5-ZNRF3/RNF43 Module in Liver Homeostasis, Regeneration, and Disease,” Hepatology 76, no. 3 (2022): 888–899.

[69] Y. Zhang and X. Wang, “Targeting the Wnt/β-catenin Signaling Pathway in Cancer,” Journal of hematology & oncology 13, no. 1 (2020): 165.

[70] C. Xue, Q. Chu, Q. Shi, Y. Zeng, J. Lu, and L. Li, “Wnt Signaling Pathways in Biology and Disease: Mechanisms and Therapeutic Advances,” Signal Transduct Target Ther 10, no. 1 (2025): 106.

[71] S. J. Schunk, J. Floege, D. Fliser, and T. Speer, “WNT-β-catenin Signalling—a Versatile Player in Kidney Injury and Repair,” Nature Reviews Nephrology 17, no. 3 (2021): 172–184.

[72] M. M. Maurice and S. Angers, “Mechanistic Insights Into Wnt-β-catenin Pathway Activation and Signal Transduction,” Nature Reviews Molecular Cell Biology 26, no. 5 (2025): 371–388.

[73] V. D. Leitch, J. H. D. Bassett, and G. R. Williams, “Role of Thyroid Hormones in Craniofacial Development,” Nature reviews Endocrinology 16, no. 3 (2020): 147–164.

[74] M. Majidinia, J. Aghazadeh, R. Jahanban-Esfahlani, and B. Yousefi, “The Roles of Wnt/β-catenin Pathway in Tissue Development and Regenerative Medicine,” Journal of Cellular Physiology 233, no. 8 (2018): 5598–5612.

[75] Prevalence and Architecture of De Novo Mutations in Developmental Disorders. Nature 2017;542(7642):433–438.

[76] J. Fortea, E. Vilaplana, M. Carmona-Iragui, et al., “Clinical and Biomarker Changes of Alzheimer's Disease in Adults With Down syndrome: A Cross-sectional Study,” Lancet 395, no. 10242 (2020): 1988–1997.

[77] A. N. Aldosari and T. S. Aldosari, “Comprehensive Evaluation of the Child With Global Developmental Delays or Intellectual Disability,” Clin Exp Pediatr 67, no. 9 (2024): 435–446.

[78] D. M. McKean, Q. Zhang, P. Narayan, et al., “Increased Endothelial Sclerostin Caused by Elevated DSCAM Mediates Multiple Trisomy 21 Phenotypes,” Journal of Clinical Investigation 134, no. 11 (2024): e167811.

[79] S. Granno, J. Nixon-Abell, D. C. Berwick, et al., “Downregulated Wnt/β-catenin Signalling in the Down syndrome Hippocampus,” Scientific Reports 9, no. 1 (2019): 7322.

[80] Y. Lu, M. Qin, Q. He, et al., “How the Extra X Chromosome Impairs the Development of Male Fetal Germ Cells,” Nature 635, no. 8040 (2024): 960–968.

[81] K. Szymanska, K. Boldt, C. V. Logan, et al., “Regulation of Canonical Wnt Signalling by the Ciliopathy Protein MKS1 and the E2 Ubiquitin-conjugating Enzyme UBE2E1,” Elife 11 (2022): e57593.

[82] Z. Chen, Y. Lei, X. Cao, et al., “Genetic Analysis of Wnt/PCP Genes in Neural Tube Defects,” BMC Med Genomics 11, no. 1 (2018): 38.

[83] N. D. Greene and A. J. Copp, “Neural Tube Defects,” Annual Review of Neuroscience 37 (2014): 221–242.

[84] H. M. Brown, S. A. Murray, H. Northrup, K. S. Au, and L. A. Niswander, “Snx3 is Important for Mammalian Neural Tube Closure via Its Role in Canonical and Non-canonical WNT Signaling,” Development (Cambridge, England) 147, no. 22 (2020): dev192518.

[85] J. Li, Q. Xie, J. Gao, et al., “Aberrant Gcm1 Expression Mediates Wnt/β-catenin Pathway Activation in Folate Deficiency Involved in Neural Tube Defects,” Cell death & disease 12, no. 3 (2021): 234.

[86] D. L. Shi, “Wnt/Planar Cell Polarity Signaling Controls Morphogenetic Movements of Gastrulation and Neural Tube Closure,” Cellular and Molecular Life Sciences 79, no. 12 (2022): 586.

[87] Y. Feng, N. Zhu, K. Bedi, et al., “SOX9 suppresses Colon Cancer via Inhibiting Epithelial-mesenchymal Transition and SOX2 Induction,” Journal of Clinical Investigation 135, no. 11 (2025): e184115.

[88] K. Peng, L. Kou, L. Yu, et al., “Histone Demethylase JMJD2D Interacts with β-Catenin to Induce Transcription and Activate Colorectal Cancer Cell Proliferation and Tumor Growth in Mice,” Gastroenterology 156, no. 4 (2019): 1112–1126.

[89] F. Hua, S. Shang, Y. W. Yang, et al., “TRIB3 Interacts with β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis,” Gastroenterology 156, no. 3 (2019): 708–721. e15.

[90] T. Rösner, C. Rupp, C. Lechler, et al., “Activation of RAS/MEK/ERK Signalling Drives Biliary Differentiation in Primary Liver Cancer,” Gut 74, no. 10 (2025): 1653–1666.

[91] Z. Qin, D. Jiang, Z. Yu, et al., “Proteogenomic Characterization Reveals That Lipid Droplet Formation Promotes Esophageal Squamous Cell Cancer Progression,” Science Translational Medicine 17, no. 802 (2025): eadt0214.

[92] T. T. Cao, D. Xiang, B. L. Liu, et al., “FZD7 is a Novel Prognostic Marker and Promotes Tumor Metastasis via WNT and EMT Signaling Pathways in Esophageal Squamous Cell Carcinoma,” Oncotarget 8, no. 39 (2017): 65957–65968.

[93] M. Saikia, H. K. Shah, D. E. Hallahan, A. K. Singh, and V. Kapoor, “Blocking the Functional Domain of Cancer Cell Surface TIP1 Upregulates Midkine via the β-catenin/Wnt Signaling Pathway,” Cancer Gene Therapy 32, no. 7 (2025): 785–792.

[94] E. Flores-Hernández, D. M. Velázquez, M. C. Castañeda-Patlán, et al., “Canonical and Non-canonical Wnt Signaling Are Simultaneously Activated by Wnts in Colon Cancer Cells,” Cell Signalling 72 (2020): 109636.

[95] Z. Li, Z. Yang, W. Liu, et al., “Disheveled3 enhanced EMT and Cancer Stem-Like Cells Properties via Wnt/β-catenin/c-Myc/SOX2 Pathway in Colorectal Cancer,” Journal of translational medicine 21, no. 1 (2023): 302.

[96] L. Zhou, J. Jiang, and Z. Huang, “Hypoxia-induced lncRNA STEAP3-AS1 Activates Wnt/β-catenin Signaling to Promote Colorectal Cancer Progression by Preventing M(6)A-mediated Degradation of STEAP3 mRNA,” Molecular cancer 21, no. 1 (2022): 168.

[97] Y. Liu, H. Lv, X. Liu, et al., “The RP11-417E7.1/THBS2 Signaling Pathway Promotes Colorectal Cancer Metastasis by Activating the Wnt/β-catenin Pathway and Facilitating Exosome-mediated M2 Macrophage Polarization,” Journal of Experimental & Clinical Cancer Research 43, no. 1 (2024): 195.

[98] J. Wang, H. Yu, W. Dong, et al., “N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance through WNT/β-Catenin and Hippo Signaling Pathways,” Gastroenterology 164, no. 6 (2023): 990–1005.

[99] A. Kaiser, G. Eiselt, J. Bechler, O. Huber, and M. Schmidt, “WNT3a Signaling Inhibits Aromatase Expression in Breast Adipose Fibroblasts-A Possible Mechanism Supporting the Loss of Estrogen Responsiveness of Triple-Negative Breast Cancers,” International Journal of Molecular Sciences 24, no. 5 (2023): 4654.

[100] N. Coupe, L. Guo, E. Bridges, et al., “WNT5A-ROR2 axis Mediates VEGF Dependence of BRAF Mutant Melanoma,” Cell Oncol (Dordr) 46, no. 2 (2023): 391–407.

[101] N. Rajakulendran, K. J. Rowland, H. J. Selvadurai, et al., “Wnt and Notch Signaling Govern Self-renewal and Differentiation in a Subset of human Glioblastoma Stem Cells,” Genes & development 33, no. 9-10 (2019): 498–510.

[102] E. Binda, A. Visioli, F. Giani, et al., “Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-Like Cells,” Cancer Research 77, no. 4 (2017): 996–1007.

[103] J. M. Wang, F. H. Zhang, H. Y. Xie, et al., “KIF26B promotes Bladder Cancer Progression via Activating Wnt/β-catenin Signaling in a TRAF2-dependent Pathway,” Cell reports 44, no. 5 (2025): 115595.

[104] S. M. Douglass, M. E. Fane, E. Sanseviero, et al., “Myeloid-Derived Suppressor Cells Are a Major Source of Wnt5A in the Melanoma Microenvironment and Depend on Wnt5A for Full Suppressive Activity,” Cancer Research 81, no. 3 (2021): 658–670.

[105] J. Bian, M. Dannappel, C. Wan, and R. Firestein, “Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer,” Cells 9, no. 9 (2020): 2125.

[106] L. Xiong, X. Yang, H. Liu, et al., “Glutamic-pyruvic Transaminase 1 Deficiency-mediated Metabolic Reprogramming Facilitates Colorectal Adenoma-carcinoma Progression,” Science Translational Medicine 17, no. 779 (2025): eadp9805.

[107] H. Tamagawa, M. Fujii, K. Togasaki, et al., “Wnt-deficient and Hypoxic Environment Orchestrates Squamous Reprogramming of human Pancreatic Ductal Adenocarcinoma,” Nature Cell Biology 26, no. 10 (2024): 1759–1772.

[108] R. Baron and M. Kneissel, “WNT Signaling in Bone Homeostasis and Disease: From human Mutations to Treatments,” Nature Medicine 19, no. 2 (2013): 179–192.

[109] F. Marini, F. Giusti, G. Palmini, and M. L. Brandi, “Role of Wnt Signaling and Sclerostin in Bone and as Therapeutic Targets in Skeletal Disorders,” Osteoporosis International 34, no. 2 (2023): 213–238.

[110] B. Zhou, J. Hu, Y. Yu, et al., “Novel Aptamers Targeting Sclerostin Loop3 Improve Skeletal and Muscle Properties without Adverse Cardiovascular Effects in Orchiectomized Mice,” J Cachexia Sarcopenia Muscle 16, no. 3 (2025): e13831.

[111] K. Kumawat and R. Gosens, “WNT-5A: Signaling and Functions in Health and Disease,” Cellular and Molecular Life Sciences 73, no. 3 (2016): 567–587.

[112] S. Suthon, J. Lin, R. S. Perkins, J. R. Crockarell,, G. A. Miranda-Carboni, and S. A. Krum, “Estrogen Receptor Alpha and NFATc1 Bind to a Bone Mineral Density-associated SNP to Repress WNT5B in Osteoblasts,” American Journal of Human Genetics 109, no. 1 (2022): 97–115.

[113] J. Luther, T. A. Yorgan, T. Rolvien, et al., “Wnt1 is an Lrp5-independent Bone-anabolic Wnt Ligand,” Science Translational Medicine 10, no. 466 (2018): eaau7137.

[114] Q. Yao, X. Wu, C. Tao, et al., “Osteoarthritis: Pathogenic Signaling Pathways and Therapeutic Targets,” Signal Transduct Target Ther 8, no. 1 (2023): 56.

[115] J. Loughlin, B. Dowling, K. Chapman, et al., “Functional Variants Within the Secreted Frizzled-related Protein 3 Gene Are Associated With Hip Osteoarthritis in Females,” PNAS 101, no. 26 (2004): 9757–9762.

[116] T. J. Dreyer, J. A. C. Keen, L. M. Wells, et al., “Porcupine Inhibition Is a Promising Pharmacological Treatment for Severe Sclerosteosis Pathologies,” Bone Res 13, no. 1 (2025): 44.

[117] M. H. van den Bosch, A. B. Blom, F. A. van de Loo, et al., “Brief Report: Induction of Matrix Metalloproteinase Expression by Synovial Wnt Signaling and Association with Disease Progression in Early Symptomatic Osteoarthritis,” Arthritis Rheumatol 69, no. 10 (2017): 1978–1983.

[118] A. S. Thorup, D. Strachan, S. Caxaria, et al., “ROR2 blockade as a Therapy for Osteoarthritis,” Science Translational Medicine 12, no. 561 (2020): eaax3063.

[119] W. Tong, Y. Zeng, D. H. K. Chow, et al., “Wnt16 attenuates Osteoarthritis Progression Through a PCP/JNK-mTORC1-PTHrP Cascade,” Annals of the Rheumatic Diseases 78, no. 4 (2019): 551–561.

[120] M. Alhashmi, A. M. E. Gremida, S. K. Maharana, et al., “Skeletal Progenitor LRP1 Deficiency Causes Severe and Persistent Skeletal Defects With Wnt Pathway Dysregulation,” Bone Res 13, no. 1 (2025): 17.

[121] H. H. Luo, W. Y. Ren, A. H. Ye, et al., “DDIT3 switches Osteogenic Potential of BMP9 to Lipogenic by Attenuating Wnt/β-catenin Signaling via Up-regulating DKK1 in Mesenchymal Stem Cells,” Aging (Albany NY) 16, no. 18 (2024): 12543–12558.

[122] M. L. Xu, C. W. C. Bi, E. Y. L. Liu, T. T. X. Dong, and K. W. K. Tsim, “Wnt3a induces the Expression of Acetylcholinesterase During Osteoblast Differentiation via the Runx2 Transcription Factor,” Journal of Biological Chemistry 292, no. 30 (2017): 12667–12678.

[123] S. Rogers and S. Scholpp, “Vertebrate Wnt5a—At the Crossroads of Cellular Signalling,” Seminars in cell & developmental biology 125 (2022): 3–10.

[124] L. Topol, X. Jiang, H. Choi, L. Garrett-Beal, P. J. Carolan, and Y. Yang, “Wnt-5a Inhibits the Canonical Wnt Pathway by Promoting GSK-3-independent Beta-catenin Degradation,” Journal of Cell Biology 162, no. 5 (2003): 899–908.

[125] N. Faraji, N. Ebadpour, M. Abavisani, and A. Gorji, “Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases,” Molecular Neurobiology 62, no. 3 (2025): 3630–3652.

[126] E. Tolosa, A. Garrido, and S. W. Scholz, “Poewe W. Challenges in the Diagnosis of Parkinson's Disease,” Lancet Neurology 20, no. 5 (2021): 385–397.

[127] S. J. Tabrizi, C. Estevez-Fraga, W. M. C. van Roon-Mom, et al., “Potential Disease-modifying Therapies for Huntington's Disease: Lessons Learned and Future Opportunities,” Lancet Neurology 21, no. 7 (2022): 645–658.

[128] P. Scheltens, B. De Strooper, M. Kivipelto, et al., “Alzheimer's Disease,” Lancet 397, no. 10284 (2021): 1577–1590.

[129] C. Tapia-Rojas and N. C. Inestrosa, “Loss of Canonical Wnt Signaling Is Involved in the Pathogenesis of Alzheimer's Disease,” Neural Regen Res 13, no. 10 (2018): 1705–1710.

[130] P. Cisternas and N. C. Inestrosa, “Brain Glucose Metabolism: Role of Wnt Signaling in the Metabolic Impairment in Alzheimer's Disease,” Neuroscience and Biobehavioral Reviews 80 (2017): 316–328.

[131] J. Folke, B. Pakkenberg, and T. Brudek, “Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer's Disease,” Molecular Neurobiology 56, no. 2 (2019): 873–891.

[132] M. H. Magdesian, M. M. Carvalho, F. A. Mendes, et al., “Amyloid-beta Binds to the Extracellular Cysteine-rich Domain of Frizzled and Inhibits Wnt/Beta-catenin Signaling,” Journal of Biological Chemistry 283, no. 14 (2008): 9359–9368.

[133] G. G. Farías, I. E. Alfaro, W. Cerpa, et al., “Wnt-5a/JNK Signaling Promotes the Clustering of PSD-95 in Hippocampal Neurons,” Journal of Biological Chemistry 284, no. 23 (2009): 15857–15866.

[134] J. Liu, F. Zhou, Y. Chen, et al., “Wnt5a protects Motor Neurons in Amyotrophic Lateral Sclerosis by Regulating the Wnt/Ca(2+) Signaling Pathway,” American journal of translational research 14, no. 8 (2022): 5343–5362.

[135] C. Silva-Alvarez, M. S. Arrázola, J. A. Godoy, D. Ordenes, and N. C. Inestrosa, “Canonical Wnt Signaling Protects Hippocampal Neurons From Aβ Oligomers: Role of Non-canonical Wnt-5a/Ca(2+) in Mitochondrial Dynamics,” Front Cell Neurosci 7 (2013): 97.

[136] Q. Wang, X. Huang, Y. Su, et al., “Activation of Wnt/β-catenin Pathway Mitigates Blood-brain Barrier Dysfunction in Alzheimer's Disease,” Brain 145, no. 12 (2022): 4474–4488.

[137] L. Z. Xu, B. Q. Li, F. Y. Li, et al., “Upregulation of Wnt2b Exerts Neuroprotective Effect by Alleviating Mitochondrial Dysfunction in Alzheimer's Disease,” CNS neuroscience & therapeutics 29, no. 7 (2023): 1805–1816.

[138] M. R. Sahu, M. H. Ahmad, and A. C. Mondal, “MST1 selective Inhibitor Xmu-mp-1 Ameliorates Neuropathological Changes in a Rat Model of Sporadic Alzheimer's Disease by Modulating Hippo-Wnt Signaling Crosstalk,” Apoptosis 29, no. 9-10 (2024): 1824–1851.

[139] P. Perez-Corredor, T. E. Vanderleest, G. N. Vacano, et al., “APOE3 Christchurch Modulates β-catenin/Wnt Signaling in iPS Cell-derived Cerebral Organoids From Alzheimer's Cases,” Front Mol Neurosci 17 (2024): 1373568.

[140] N. Gamit, A. Dharmarajan, G. Sethi, and S. Warrier, “Want of Wnt in Parkinson's Disease: Could sFRP Disrupt Interplay Between Nurr1 and Wnt Signaling?,” Biochemical Pharmacology 212 (2023): 115566.

[141] B. Marchetti, “Wnt/β-Catenin Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson's Disease,” International Journal of Molecular Sciences 19, no. 12 (2018).

[142] A. Serafino and M. Cozzolino, “The Wnt/β-catenin Signaling: A Multifunctional Target for Neuroprotective and Regenerative Strategies in Parkinson's disease,” Neural Regen Res 18, no. 2 (2023): 306–308.

[143] Y. L. Huang, J. N. Zhang, T. Z. Hou, L. Gu, H. M. Yang, and H. Zhang, “Inhibition of Wnt/β-catenin Signaling Attenuates Axonal Degeneration in Models of Parkinson's Disease,” Neurochemistry International 159 (2022): 105389.

[144] A. Mishra, S. Singh, V. Tiwari, Parul, and S. Shukla, “Dopamine D1 Receptor Activation Improves Adult Hippocampal Neurogenesis and Exerts Anxiolytic and Antidepressant-Like Effect via Activation of Wnt/β-catenin Pathways in Rat Model of Parkinson's Disease,” Neurochemistry International 122 (2019): 170–186.

[145] S. Singh, A. Mishra, S. J. Mohanbhai, et al., “Axin-2 Knockdown Promote Mitochondrial Biogenesis and Dopaminergic Neurogenesis by Regulating Wnt/β-catenin Signaling in Rat Model of Parkinson's Disease,” Free Radic Biol Med 129 (2018): 73–87.

[146] A. Wetzel, S. H. Lei, T. Liu, et al., “Dysregulated Wnt and NFAT Signaling in a Parkinson's Disease LRRK2 G2019S Knock-in Model,” Scientific Reports 14, no. 1 (2024): 12393.

[147] J. M. Haynes, S. M. Sibuea, A. A. Aguiar, F. Li, J. K. Ho, and C. W. Pouton, “Inhibition of β-catenin Dependent WNT Signalling Upregulates the Transcriptional Repressor NR0B1 and Downregulates Markers of an A9 Phenotype in human Embryonic Stem Cell-derived Dopaminergic Neurons: Implications for Parkinson's Disease,” PLoS ONE 16, no. 12 (2021): e0261730.

[148] E. Arenas, “Wnt Signaling in Midbrain Dopaminergic Neuron Development and Regenerative Medicine for Parkinson's disease,” Journal of Molecular Cell Biology 6, no. 1 (2014): 42–53.

[149] F. L'Episcopo, C. Tirolo, N. Testa, et al., “Reactive Astrocytes and Wnt/β-catenin Signaling Link Nigrostriatal Injury to Repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Model of Parkinson's Disease,” Neurobiology of Disease 41, no. 2 (2011): 508–527.

[150] J. D. Godin, G. Poizat, M. A. Hickey, F. Maschat, and S. Humbert, “Mutant Huntingtin-impaired Degradation of Beta-catenin Causes Neurotoxicity in Huntington's disease,” Embo Journal 29, no. 14 (2010): 2433–2445.

[151] T. J. Krzystek, R. Rathnayake, J. Zeng, et al., “Opposing Roles for GSK3β and ERK1-dependent Phosphorylation of Huntingtin During Neuronal Dysfunction and Cell Death in Huntington's Disease,” Cell death & disease 16, no. 1 (2025): 328.

[152] C. Smith-Geater, S. J. Hernandez, R. G. Lim, et al., “Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation,” Stem Cell Reports 14, no. 3 (2020): 406–419.

[153] R. G. Lim, C. Quan, and A. M. Reyes-Ortiz, “Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits,” Cell reports 19, no. 7 (2017): 1365–1377.

[154] E. M. Elbaz, H. S. Helmy, A. E. El-Sahar, M. A. Saad, and R. H. Sayed, “Lercanidipine Boosts the Efficacy of Mesenchymal Stem Cell Therapy in 3-NP-induced Huntington's disease Model Rats via Modulation of the Calcium/Calcineurin/NFATc4 and Wnt/β-catenin Signalling Pathways,” Neurochemistry International 131 (2019): 104548.

[155] A. de Zawadzki, D. J. Leeming, A. J. Sanyal, et al., “Hot and Cold Fibrosis: The Role of Serum Biomarkers to Assess Immune Mechanisms and ECM-cell Interactions in human Fibrosis,” Journal of Hepatology 83, no. 1 (2025): 239–257.

[156] F. Rieder, L. E. Nagy, T. M. Maher, et al., “Fibrosis: Cross-organ Biology and Pathways to Development of Innovative Drugs,” Nat Rev Drug Discovery 24, no. 7 (2025): 543–569.

[157] J. Wang, K. Li, D. Hao, et al., “Pulmonary Fibrosis: Pathogenesis and Therapeutic Strategies,” MedComm 5, no. 10 (2024): e744.

[158] P. Pakshir and B. Hinz, “The Big Five in Fibrosis: Macrophages, Myofibroblasts, Matrix, Mechanics, and Miscommunication,” Matrix Biology 68-69 (2018): 81–93.

[159] A. Santos and D. Lagares, “Matrix Stiffness: The Conductor of Organ Fibrosis,” Current Rheumatology Reports 20, no. 1 (2018): 2.

[160] J. N. Murdoch, D. J. Henderson, K. Doudney, et al., “Disruption of Scribble (Scrb1) Causes Severe Neural Tube Defects in the Circletail Mouse,” Human Molecular Genetics 12, no. 2 (2003): 87–98.

[161] Y. Feng, Y. Liang, X. Zhu, et al., “The Signaling Protein Wnt5a Promotes TGFβ1-mediated Macrophage Polarization and Kidney Fibrosis by Inducing the Transcriptional Regulators Yap/Taz,” Journal of Biological Chemistry 293, no. 50 (2018): 19290–19302.

[162] J. Y. Song, F. Wehbe, A. K. Wong, et al., “YAP/TAZ Activity in PDGFRα-expressing Alveolar Fibroblasts Modulates AT2 Proliferation Through Wnt4,” Cell reports 44, no. 5 (2025): 115645.

[163] M. M. Mia, S. Ghani, D. M. Cibi, et al., “YAP/TAZ Are Crucial Regulators of Macrophage-mediated Pulmonary Inflammation and Fibrosis After Bleomycin-induced Injury,” European Respiratory Journal 65, no. 6 (2025): 2301544.

[164] L. Sun, X. Zhang, S. Wu, et al., “Dynamic Interplay Between IL-1 and WNT Pathways in Regulating Dermal Adipocyte Lineage Cells During Skin Development and Wound Regeneration,” Cell reports 42, no. 6 (2023): 112647.

[165] B. Mao, W. Wu, G. Davidson, et al., “Kremen Proteins Are Dickkopf Receptors That Regulate Wnt/Beta-catenin Signalling,” Nature 417, no. 6889 (2002): 664–667.

[166] B. Mao and C. Niehrs, “Kremen2 modulates Dickkopf2 Activity During Wnt/LRP6 Signaling,” Gene 302, no. 1-2 (2003): 179–183.

[167] C. L. Lin, J. Y. Wang, J. Y. Ko, Y. T. Huang, Y. H. Kuo, and F. S. Wang, “Dickkopf-1 Promotes Hyperglycemia-induced Accumulation of Mesangial Matrix and Renal Dysfunction,” Journal of the American Society of Nephrology 21, no. 1 (2010): 124–135.

[168] S. Y. Ren, B. G. Johnson, Y. Kida, et al., “LRP-6 Is a Coreceptor for Multiple Fibrogenic Signaling Pathways in Pericytes and Myofibroblasts That Are Inhibited by DKK-1,” P Natl Acad Sci USA 110, no. 4 (2013): 1440–1445.

[169] Y. C. Hsu, C. Ho, Y. H. Shih, et al., “Knockout of KLF10 Ameliorated Diabetic Renal Fibrosis via Downregulation of DKK-1,” Molecules (Basel, Switzerland) 27, no. 9 (2022): 2644.

[170] G. Federico, M. Meister, D. Mathow, et al., “Tubular Dickkopf-3 Promotes the Development of Renal Atrophy and Fibrosis,” JCI Insight 1, no. 1 (2016): e84916.

[171] S. Svegliati, G. Marrone, A. Pezone, et al., “Oxidative DNA Damage Induces the ATM-mediated Transcriptional Suppression of the Wnt Inhibitor WIF-1 in Systemic Sclerosis and Fibrosis,” Science signaling 7, no. 341 (2014): ra84.

[172] J. M. Sha, R. Q. Zhang, X. C. Wang, et al., “Epigenetic Reader MeCP2 Repressed WIF1 Boosts Lung Fibroblast Proliferation, Migration and Pulmonary Fibrosis,” Toxicology Letters 381 (2023): 1–12.

[173] M. A. Zaafan and A. M. Abdelhamid, “Dasatinib Ameliorates Thioacetamide-induced Liver Fibrosis: Modulation of miR-378 and miR-17 and Their Linked Wnt/Beta-catenin and TGF-beta/Smads Pathways,” Journal of Enzyme Inhibition and Medicinal Chemistry 37, no. 1 (2022): 118–124.

[174] T. L. Stanley, L. T. Fourman, I. Zheng, et al., “Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease,” Journal of Clinical Endocrinology and Metabolism 106, no. 2 (2021): e520–e533.

[175] R. Wang, B. Feng, Q. Yao, et al., “Human Placenta Mesenchymal Stromal Cells Alleviate Intestinal Inflammation and Repair Intestinal Barrier Function by Activating AMPK-FXR Pathway,” Communications Biology 8, no. 1 (2025): 830.

[176] S. Namvar, A. S. Woolf, L. A. Zeef, T. Wilm, B. Wilm, and S. E. Herrick, “Functional Molecules in Mesothelial-to-mesenchymal Transition Revealed by Transcriptome Analyses,” Journal of Pathology 245, no. 4 (2018): 491–501.

[177] Y. Su, T. Nishimoto, S. Hoffman, X. X. Nguyen, and J. M. Pilewski, “Feghali-Bostwick C. Insulin-Like Growth Factor Binding Protein-4 Exerts Antifibrotic Activity by Reducing Levels of Connective Tissue Growth Factor and the C-X-C Chemokine Receptor 4,” FASEB Bioadv 1, no. 3 (2019): 167–179.

[178] M. Katoh, “Multi‑Layered Prevention and Treatment of Chronic Inflammation, Organ Fibrosis and Cancer Associated With Canonical WNT/Beta‑Catenin Signaling Activation (Review),” International Journal of Molecular Medicine 42, no. 2 (2018): 713–725.

[179] G. Belenguer, G. Mastrogiovanni, C. Pacini, et al., “RNF43/ZNRF3 loss Predisposes to Hepatocellular-carcinoma by Impairing Liver Regeneration and Altering the Liver Lipid Metabolic Ground-state,” Nature Communications 13, no. 1 (2022): 334.

[180] T. Sun, S. Annunziato, S. Bergling, et al., “ZNRF3 and RNF43 Cooperate to Safeguard Metabolic Liver Zonation and Hepatocyte Proliferation,” Cell Stem Cell 28, no. 10 (2021): 1822–1837. e10.

[181] E. Saponara, C. Penno, V. Orsini, et al., “Loss of Hepatic Leucine-Rich Repeat-Containing G-Protein Coupled Receptors 4 and 5 Promotes Nonalcoholic Fatty Liver Disease,” American Journal of Pathology 193, no. 2 (2023): 161–181.

[182] W. Li, X. Yu, C. Zhu, et al., “Notum Attenuates HBV-related Liver Fibrosis Through Inhibiting Wnt 5a Mediated Non-canonical Pathways,” Biological Research 52, no. 1 (2019): 10.

[183] F. Guo, M. Seldin, M. Peterfy, et al., “NOTUM Promotes Thermogenic Capacity and Protects Against Diet-induced Obesity in Male Mice,” Scientific Reports 11, no. 1 (2021): 16409.

[184] J. Green, R. Nusse, and R. van Amerongen, “The Role of Ryk and Ror Receptor Tyrosine Kinases in Wnt Signal Transduction,” Cold Spring Harbor perspectives in biology 6, no. 2 (2014): a009175.

[185] K. Kamizaki, Y. Minami, and M. Nishita, “Role of the Ror family Receptors in Wnt5a Signaling,” In Vitro Cellular & Developmental Biology Animal 60, no. 5 (2024): 489–501.

[186] N. W. Chavkin, S. Sano, Y. Wang, et al., “The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation,” Journal of the American Heart Association 10, no. 13 (2021): e019904.

[187] L. J. Vuga, A. Ben-Yehudah, E. Kovkarova-Naumovski, et al., “WNT5A is a Regulator of Fibroblast Proliferation and Resistance to Apoptosis,” American Journal of Respiratory Cell and Molecular Biology 41, no. 5 (2009): 583–589.

[188] M. d'Alessandro, P. Soccio, L. Bergantini, et al., “Extracellular Vesicle Surface Signatures in IPF Patients: A Multiplex Bead-Based Flow Cytometry Approach,” Cells 10, no. 5 (2021): 1045.

[189] C. Li, S. M. Smith, N. Peinado, et al., “WNT5a-ROR Signaling Is Essential for Alveologenesis,” Cells 9, no. 2 (2020): 384.

[190] H. Kobayashi, H. C. Looker, and E. Satake, “Results of Untargeted Analysis Using the SOMAscan Proteomics Platform Indicates Novel Associations of Circulating Proteins With Risk of Progression to Kidney Failure in Diabetes,” Kidney International 102, no. 2 (2022): 370–381.

[191] D. Liu, J. Du, H. Xie, et al., “Wnt5a/beta-catenin-mediated Epithelial-mesenchymal Transition: A Key Driver of Subretinal Fibrosis in Neovascular Age-related Macular Degeneration,” J Neuroinflammation 21, no. 1 (2024): 75.

[192] M. Padwal, L. Liu, and P. J. Margetts, “The Role of WNT5A and Ror2 in Peritoneal Membrane Injury,” Journal of Cellular and Molecular Medicine 24, no. 6 (2020): 3481–3491.

[193] A. C. van Vliet, J. Lee, M. van der Poel, et al., “Coordinated Changes in the Expression of Wnt Pathway Genes Following human and Rat Peripheral Nerve Injury,” PLoS ONE 16, no. 4 (2021): e0249748.

[194] Z. Shen, B. Feng, W. L. Lim, et al., “Astrocytic Ryk Signaling Coordinates Scarring and Wound Healing After Spinal Cord Injury,” PNAS 122, no. 15 (2025): e2417400122.

[195] J. H. Cheng, H. She, Y. P. Han, et al., “Wnt Antagonism Inhibits Hepatic Stellate Cell Activation and Liver Fibrosis,” American journal of physiology Gastrointestinal and liver physiology 294, no. 1 (2008): G39–G49.

[196] Y. Xinguang, Y. Huixing, W. Xiaowei, W. Xiaojun, and Y. Linghua, “R-spondin1 Arguments Hepatic Fibrogenesis in Vivo and in Vitro,” Journal of Surgical Research 193, no. 2 (2015): 598–605.

[197] X. Su, G. Zhou, M. Tian, S. Wu, and Y. Wang, “Silencing of RSPO1 Mitigates Obesity-related Renal Fibrosis in Mice by Deactivating Wnt/Beta-catenin Pathway,” Experimental Cell Research 405, no. 2 (2021): 112713.

[198] Y. Dang, B. Liu, P. Xu, et al., “Gpr48 deficiency Induces Polycystic Kidney Lesions and Renal Fibrosis in Mice by Activating Wnt Signal Pathway,” PLoS ONE 9, no. 3 (2014): e89835.

[199] A. Sugimoto, Y. Saito, G. Wang, et al., “Hepatic Stellate Cells Control Liver Zonation, Size and Functions via R-spondin 3,” Nature 640, no. 8059 (2025): 752–761.

[200] Y. Geng and R. F. Schwabe, “Hepatic Stellate Cell Heterogeneity: Functional Aspects and Therapeutic Implications,” Hepatology (2025).

[201] R. Ando, Y. Shiraki, Y. Miyai, et al., “Meflin Is a Marker of Pancreatic Stellate Cells Involved in Fibrosis and Epithelial Regeneration in the Pancreas,” Journal of Pathology 262, no. 1 (2024): 61–75.

[202] A. W. Chua, D. Ma, S. U. Gan, et al., “The Role of R-spondin2 in Keratinocyte Proliferation and Epidermal Thickening in Keloid Scarring,” Journal of Investigative Dermatology 131, no. 3 (2011): 644–654.

[203] A. Munguia-Reyes, Y. I. Balderas-Martinez, C. Becerril, et al., “R-Spondin-2 Is Upregulated in Idiopathic Pulmonary Fibrosis and Affects Fibroblast Behavior,” American Journal of Respiratory Cell and Molecular Biology 59, no. 1 (2018): 65–76.

[204] C. Gur, S. Y. Wang, F. Sheban, et al., “LGR5 expressing Skin Fibroblasts Define a Major Cellular Hub Perturbed in Scleroderma,” Cell 185, no. 8 (2022): 1373–1388. e20.

[205] Y. Lin, Z. P. Fang, H. J. Liu, et al., “HGF/R-spondin1 Rescues Liver Dysfunction Through the Induction of Lgr5(+) Liver Stem Cells,” Nature Communications 8, no. 1 (2017): 1175.

[206] Z. Dai, G. Song, A. Balakrishnan, et al., “Growth Differentiation Factor 11 Attenuates Liver Fibrosis via Expansion of Liver Progenitor Cells,” Gut 69, no. 6 (2020): 1104–1115.

[207] Y. Gao, W. Zhai, L. Sun, et al., “Hepatic LGR4 Aggravates Cholestasis-induced Liver Injury in Mice,” American journal of physiology Gastrointestinal and liver physiology 326, no. 4 (2024): G460–G472.

[208] Y. Liu, J. W. Song, J. Y. Lin, R. Miao, and J. C. Zhong, “Roles of MicroRNA-122 in Cardiovascular Fibrosis and Related Diseases,” Cardiovascular Toxicology 20, no. 5 (2020): 463–473.

[209] Q. Lu, M. Tan, Q. Hou, M. Wang, and C. Dai, “PP2A Catalytic Subunit Alpha Promotes Fibroblast Activation and Kidney Fibrosis via ERK Pathway,” Cell Signalling 90 (2022): 110187.

[210] Y. Sun, B. Li, B. Song, et al., “UHRF1 promotes Calcium Oxalate-induced Renal Fibrosis by Renal Lipid Deposition via Bridging AMPK Dephosphorylation,” Cell Biology and Toxicology 41, no. 1 (2025): 39.

[211] K. Prasad, D. Bhattacharya, S. G. E. Shams, et al., “Kisspeptin Alleviates Human Hepatic Fibrogenesis by Inhibiting TGFbeta Signaling in Hepatic Stellate Cells,” Cells 13, no. 19 (2024): 1651.

[212] L. Chen, P. Guo, W. Li, et al., “Perturbation of Specific Signaling Pathways Is Involved in Initiation of Mouse Liver Fibrosis,” Hepatology 73, no. 4 (2021): 1551–1569.

[213] K. Lu, S. Y. Shen, O. Y. Luo, et al., “Manipulating PP2Acalpha-ASK-JNK Signaling to Favor Apoptotic Over Necroptotic Hepatocyte Fate Reduces the Extent of Necrosis and Fibrosis Upon Acute Liver Injury,” Cell death & disease 13, no. 11 (2022): 985.

[214] S. Yoon, T. Kook, H. K. Min, et al., “PP2A negatively Regulates the Hypertrophic Response by Dephosphorylating HDAC2 S394 in the Heart,” Experimental & Molecular Medicine 50, no. 7 (2018): 1–14.

[215] M. Hoehn, Y. Zhang, J. Xu, et al., “Overexpression of Protein Phosphatase 2A in a Murine Model of Chronic Myocardial Infarction Leads to Increased Adverse Remodeling but Restores the Regulation of Beta-catenin by Glycogen Synthase Kinase 3beta,” International Journal of Cardiology 183 (2015): 39–46.

[216] W. Zhang, K. Zhang, Y. Ma, et al., “Secreted Frizzled-related Proteins: A Promising Therapeutic Target for Cancer Therapy Through Wnt Signaling Inhibition,” Biomedicine & Pharmacotherapy 166 (2023): 115344.

[217] S. E. Jones and C. Jomary, “Secreted Frizzled-related Proteins: Searching for Relationships and Patterns,” BioEssays 24, no. 9 (2002): 811–820.

[218] A. Rattner, J. C. Hsieh, P. M. Smallwood, et al., “A family of Secreted Proteins Contains Homology to the Cysteine-rich Ligand-binding Domain of Frizzled Receptors,” PNAS 94, no. 7 (1997): 2859–2863.

[219] R. A. Bhat, B. Stauffer, B. S. Komm, and P. V. Bodine, “Structure-function Analysis of Secreted Frizzled-related Protein-1 for Its Wnt Antagonist Function,” Journal of Cellular Biochemistry 102, no. 6 (2007): 1519–1528.

[220] L. Bányai and L. Patthy, “The NTR Module: Domains of Netrins, Secreted Frizzled Related Proteins, and Type I Procollagen C-proteinase Enhancer Protein Are Homologous With Tissue Inhibitors of Metalloproteases,” Protein Science 8, no. 8 (1999): 1636–1642.

[221] H. Owji, N. Nezafat, M. Negahdaripour, A. Hajiebrahimi, and Y. Ghasemi, “A Comprehensive Review of Signal Peptides: Structure, Roles, and Applications,” European Journal of Cell Biology 97, no. 6 (2018): 422–441.

[222] A. Huang and Y. Huang, “Role of Sfrps in Cardiovascular Disease,” Ther Adv Chronic Dis 11 (2020): 2040622320901990.

[223] M. W. Bergmann, “WNT Signaling in Adult Cardiac Hypertrophy and Remodeling: Lessons Learned From Cardiac Development,” Circulation Research 107, no. 10 (2010): 1198–1208.

[224] S. Foulquier, E. P. Daskalopoulos, G. Lluri, K. C. M. Hermans, A. Deb, and W. M. Blankesteijn, “WNT Signaling in Cardiac and Vascular Disease,” Pharmacological Reviews 70, no. 1 (2018): 68–141.

[225] L. M. Galli, T. Barnes, T. Cheng, et al., “Differential Inhibition of Wnt-3a by Sfrp-1, Sfrp-2, and Sfrp-3,” Developmental Dynamics 235, no. 3 (2006): 681–690.

[226] J. Rodriguez, P. Esteve, C. Weinl, et al., “SFRP1 regulates the Growth of Retinal Ganglion Cell Axons Through the Fz2 Receptor,” Nature Neuroscience 8, no. 10 (2005): 1301–1309.

[227] K. Yoshino, J. S. Rubin, K. G. Higinbotham, et al., “Secreted Frizzled-related Proteins Can Regulate Metanephric Development,” Mechanisms of Development 102, no. 1-2 (2001): 45–55.

[228] A. Kispert, S. Vainio, and A. P. McMahon, “Wnt-4 Is a Mesenchymal Signal for Epithelial Transformation of Metanephric Mesenchyme in the Developing Kidney,” Development (Cambridge, England) 125, no. 21 (1998): 4225–4234.

[229] W. He, L. Zhang, A. Ni, et al., “Exogenously Administered Secreted Frizzled Related Protein 2 (Sfrp2) Reduces Fibrosis and Improves Cardiac Function in a Rat Model of Myocardial Infarction,” PNAS 107, no. 49 (2010): 21110–21115.

[230] D. E. Vatner, M. Oydanich, J. Zhang, D. Babici, and S. F. Vatner, “Secreted Frizzled-related Protein 2, a Novel Mechanism to Induce Myocardial Ischemic Protection Through Angiogenesis,” Basic Research in Cardiology 115, no. 4 (2020): 48.

[231] D. Routledge and S. Scholpp, “Mechanisms of Intercellular Wnt Transport,” Development (Cambridge, England) 146, no. 10 (2019): dev176073.

[232] J. M. Chong, A. Uren, J. S. Rubin, and D. W. Speicher, “Disulfide Bond Assignments of Secreted Frizzled-related Protein-1 Provide Insights About Frizzled Homology and Netrin Modules,” Journal of Biological Chemistry 277, no. 7 (2002): 5134–5144.

[233] S. B. Russell, J. D. Russell, K. M. Trupin, et al., “Epigenetically Altered Wound Healing in Keloid Fibroblasts,” Journal of Investigative Dermatology 130, no. 10 (2010): 2489–2496.

[234] J. Liu, H. Zhu, H. Wang, et al., “Methylation of Secreted Frizzled-related Protein 1 (SFRP1) Promoter Downregulates Wnt/Beta-catenin Activity in Keloids,” Journal of Molecular Histology 49, no. 2 (2018): 185–193.

[235] S. Zhou, L. Chen, M. Mashrah, et al., “Deregulation of Secreted Frizzled-related Proteins Is Associated With Aberrant Beta-catenin Activation in the Carcinogenesis of Oral Submucous Fibrosis,” Onco Targets Ther 8 (2015): 2923–2931.

[236] R. Zhou, L. Yin, X. Zhang, and K. Zhu, “SFRP1 reduces Neutrophil Infiltration and Inhibits the Wnt/Beta-catenin Pathway to Alleviate Oral Submucous Fibrosis,” In Vitro Cellular & Developmental Biology Animal 60, no. 9 (2024): 1034–1045.

[237] J. Zhou, Z. Yi, and Q. Fu, “Dynamic Decreased Expression and Hypermethylation of Secreted Frizzled-related Protein 1 and 4 Over the Course of Pulmonary Fibrosis in Mice,” Life Sciences 218 (2019): 241–252.

[238] Y. Yu, X. Guan, L. Nie, et al., “DNA Hypermethylation of sFRP5 Contributes to Indoxyl Sulfate-induced Renal Fibrosis,” J Mol Med (Berl) 95, no. 6 (2017): 601–613.

[239] C. Dees, I. Schlottmann, R. Funke, et al., “The Wnt Antagonists DKK1 and SFRP1 Are Downregulated by Promoter Hypermethylation in Systemic Sclerosis,” Annals of the Rheumatic Diseases 73, no. 6 (2014): 1232–1239.

[240] A. M. Ascensión, S. Fuertes-Álvarez, O. Ibañez-Solé, A. Izeta, and M. J. Araúzo-Bravo, “Human Dermal Fibroblast Subpopulations Are Conserved Across Single-Cell RNA Sequencing Studies,” Journal of Investigative Dermatology 141, no. 7 (2021): 1735–1744. e35.

[241] L. Sole-Boldo, G. Raddatz, S. Schutz, et al., “Single-cell Transcriptomes of the human Skin Reveal Age-related Loss of Fibroblast Priming,” Communications Biology 3, no. 1 (2020): 188.

[242] T. Tabib, C. Morse, T. Wang, W. Chen, and R. Lafyatis, “SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin,” Journal of Investigative Dermatology 138, no. 4 (2018): 802–810.

[243] G. Theocharidis, B. E. Thomas, D. Sarkar, et al., “Single Cell Transcriptomic Landscape of Diabetic Foot Ulcers,” Nature Communications 13, no. 1 (2022): 181.

[244] J. Liu, H. Zhu, H. Wang, et al., “Methylation of Secreted Frizzled-related Protein 1 (SFRP1) Promoter Downregulates Wnt/β-catenin Activity in Keloids,” Journal of Molecular Histology 49, no. 2 (2018): 185–193.

[245] D. M. Dolivo, A. E. Rodrigues, L. S. Sun, T. A. Mustoe, S. J. Hong, and R. D. Galiano, “Skin Fibrosis Is Accompanied by Increased Expression of Secreted Frizzled-related Protein-2,” Wound Repair and Regeneration 32, no. 5 (2024): 720–724.

[246] L. Chen, Z. Wang, S. Li, G. Zhao, M. Tian, and Z. Sun, “SFRP2 and Slug Contribute to Cellular Resistance to Apoptosis in Hypertrophic Scars,” PLoS ONE 7, no. 12 (2012): e50229.

[247] K. Zhang, B. Zhang, Y. Lu, et al., “Slug Inhibition Upregulates Radiation-induced PUMA Activity Leading to Apoptosis in Cholangiocarcinomas,” Medical Oncology 28 (2011): S301–S309. Suppl 1.

[248] Q. Zhu, W. Guo, S. Zhang, et al., “Synergistic Effect of PCPE1 and sFRP2 on the Processing of Procollagens via BMP1,” Febs Letters 593, no. 7 (2019): 760.

[249] K. R. van Straalen, F. Ma, P. S. Tsou, et al., “Single-cell Sequencing Reveals Hippo Signaling as a Driver of Fibrosis in Hidradenitis Suppurativa,” Journal of Clinical Investigation 134, no. 3 (2024): e169225.

[250] H. Kida, J. J. Jiang, Y. Matsui, et al., “Dupuytren's Contracture-associated SNPs Increase SFRP4 Expression in Non-immune Cells Including Fibroblasts to Enhance Inflammation Development,” International Immunology 35, no. 7 (2023): 303–312.

[251] R. Jin, W. Zhu, J. Xu, J. Gu, and A. Deng, “Effect of Nanoparticle-mediated Delivery of SFRP4 siRNA for Treating Dupuytren Disease,” Gene Therapy 30, no. 1-2 (2023): 31–40.

[252] S. Zhou, L. Chen, M. Mashrah, et al., “Deregulation of Secreted Frizzled-related Proteins Is Associated With Aberrant β-catenin Activation in the Carcinogenesis of Oral Submucous Fibrosis,” Onco Targets Ther 8 (2015): 2923–2931.

[253] R. Zhou, L. Yin, X. Zhang, and K. Zhu, “SFRP1 reduces Neutrophil Infiltration and Inhibits the Wnt/β-catenin Pathway to Alleviate Oral Submucous Fibrosis,” In Vitro Cellular & Developmental Biology Animal 60, no. 9 (2024): 1034–1045.

[254] H. Wang, Y. Liu, X. Liang, et al., “Effects of Secreted Frizzled-related Protein 1 on Inhibiting Cardiac Remodeling,” European Review for Medical and Pharmacological Sciences 24, no. 11 (2020): 6270–6278.

[255] Z. D. Bie, L. Y. Sun, C. L. Geng, et al., “MiR-125b Regulates SFRP5 Expression to Promote Growth and Activation of Cardiac Fibroblasts,” Cell Biology International 40, no. 11 (2016): 1224–1234.

[256] L. Y. Sun, J. C. Zhao, X. M. Ge, H. Zhang, C. M. Wang, and Z. D. Bie, “Circ_LAS1L regulates Cardiac Fibroblast Activation, Growth, and Migration Through miR-125b/SFRP5 Pathway,” Cell Biochemistry and Function 38, no. 4 (2020): 443–450.

[257] J. Tao, X. Wei, Y. Huang, et al., “Sfrp1 protects Against Acute Myocardial Ischemia (AMI) Injury in Aged Mice by Inhibiting the Wnt/β-catenin Signaling Pathway,” J Cardiothorac Surg 16, no. 1 (2021): 12.

[258] M. Mirotsou, Z. Zhang, and A. Deb, “Secreted Frizzled Related Protein 2 (Sfrp2) Is the Key Akt-mesenchymal Stem Cell-released Paracrine Factor Mediating Myocardial Survival and Repair,” PNAS 104, no. 5 (2007): 1643–1648.

[259] W. Y. Wei, Q. Zhao, W. Z. Zhang, et al., “Secreted Frizzled-related Protein 2 Prevents Pressure-overload-induced Cardiac Hypertrophy by Targeting the Wnt/β-catenin Pathway,” Molecular and Cellular Biochemistry 472, no. 1-2 (2020): 241–251.

[260] Y. Gu, Y. Ding, X. Zhang, Y. Li, and Z. Shang, “Secreted Frizzled-related Protein 3 Alleviated Cardiac Remodeling Induced by Angiotensin II via Inhibiting Oxidative Stress and Apoptosis in Mice,” European Journal of Pharmacology 934 (2022): 175303.

[261] K. Matsushima, T. Suyama, C. Takenaka, et al., “Secreted Frizzled Related Protein 4 Reduces Fibrosis Scar Size and Ameliorates Cardiac Function After Ischemic Injury,” Tissue Engineering Part A 16, no. 11 (2010): 3329–3341.

[262] X. Huang, Y. Yan, W. Zheng, et al., “Secreted Frizzled-Related Protein 5 Protects against Cardiac Rupture and Improves Cardiac Function through Inhibiting Mitochondrial Dysfunction,” Frontiers in Cardiovascular Medicine 8 (2021): 682409.

[263] M. P. Alfaro, M. Pagni, A. Vincent, et al., “The Wnt Modulator sFRP2 Enhances Mesenchymal Stem Cell Engraftment, Granulation Tissue Formation and Myocardial Repair,” PNAS 105, no. 47 (2008): 18366–18371.

[264] N. Ding and C. Zheng, “Secreted Frizzled-related Protein 5 Promotes Angiogenesis of human Umbilical Vein Endothelial Cells and Alleviates Myocardial Injury in Diabetic Mice With Myocardial Infarction by Inhibiting Wnt5a/JNK Signaling,” Bioengineered 13, no. 5 (2022): 11656–11667.

[265] Z. Alvandi, Y. Nagata, L. S. A. Passos, et al., “Wnt Site Signaling Inhibitor Secreted Frizzled-Related Protein 3 Protects Mitral Valve Endothelium from Myocardial Infarction-Induced Endothelial-to-Mesenchymal Transition,” Journal of the American Heart Association 11, no. 7 (2022): e023695.

[266] H. Lin, M. Angeli, K. J. Chung, C. Ejimadu, A. R. Rosa, and T. Lee, “sFRP2 activates Wnt/β-catenin Signaling in Cardiac Fibroblasts: Differential Roles in Cell Growth, Energy Metabolism, and Extracellular Matrix Remodeling,” American Journal of Physiology. Cell Physiology 311, no. 5 (2016): C710–c719.

[267] W. Zeng, Y. Cao, W. Jiang, G. Kang, J. Huang, and S. Xie, “Knockdown of Sfrp4 Attenuates Apoptosis to Protect Against Myocardial Ischemia/Reperfusion Injury,” Journal of Pharmacological Sciences 140, no. 1 (2019): 14–19.

[268] C. H. Mayr, A. Sengupta, S. Asgharpour, et al., “Sfrp1 inhibits Lung Fibroblast Invasion During Transition to Injury-induced Myofibroblasts,” European Respiratory Journal 63, no. 2 (2024): 2301326.

[269] T. Shiomi, P. Sklepkiewicz, P. V. Bodine, and J. M. D'Armiento, “Maintenance of the Bronchial Alveolar Stem Cells in an Undifferentiated state by Secreted Frizzled-related Protein 1,” Faseb Journal 28, no. 12 (2014): 5242–5249.

[270] O. Burgy, C. H. Mayr, and D. Schenesse, “Fibroblast-derived Extracellular Vesicles Contain SFRP1 and Mediate Pulmonary Fibrosis,” JCI Insight 9, no. 18 (2024): e168889.

[271] Y. Wang, X. Fan, N. Lei, et al., “A MicroRNA Derived from Schistosoma Japonicum Promotes Schistosomiasis Hepatic Fibrosis by Targeting Host Secreted Frizzled-Related Protein 1,” Frontiers in Cellular and Infection Microbiology 10 (2020): 101.

[272] S. J. Myung, J. H. Yoon, G. Y. Gwak, et al., “Wnt Signaling Enhances the Activation and Survival of human Hepatic Stellate Cells,” Febs Letters 581, no. 16 (2007): 2954–2958.

[273] N. Chatani, Y. Kamada, T. Kizu, et al., “Secreted Frizzled-related Protein 5 (Sfrp5) Decreases Hepatic Stellate Cell Activation and Liver Fibrosis,” Liver International 35, no. 8 (2015): 2017–2026.

[274] M. Shi, P. Tian, Z. Liu, et al., “MicroRNA-27a Targets Sfrp1 to Induce Renal Fibrosis in Diabetic Nephropathy by Activating Wnt/β-Catenin Signalling,” Bioscience Reports 40, no. 6 (2020): BSR20192794.

[275] M. Matsuyama, A. Nomori, K. Nakakuni, A. Shimono, and M. Fukushima, “Secreted Frizzled-related Protein 1 (Sfrp1) Regulates the Progression of Renal Fibrosis in a Mouse Model of Obstructive Nephropathy,” Journal of Biological Chemistry 289, no. 45 (2014): 31526–31533.

[276] D. Deng, D. Tian, Y. Wang, Y. Bai, Z. Diao, and W. Liu, “Secreted Frizzled-related Protein 5 Protects Against Renal Fibrosis by Inhibiting Wnt/β-catenin Pathway,” Open Med (Wars) 19, no. 1 (2024): 20240934.

[277] H. Zhu, H. Luo, B. Skaug, et al., “Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations With Clinical Features,” Journal of Investigative Dermatology 144, no. 6 (2024): 1251–1261. e13.

[278] T. Tabib, M. Huang, N. Morse, et al., “Myofibroblast Transcriptome Indicates SFRP2(hi) Fibroblast Progenitors in Systemic Sclerosis Skin,” Nature Communications 12, no. 1 (2021): 4384.

[279] M. Trenkmann, M. Brock, R. E. Gay, et al., “Expression and Function of EZH2 in Synovial Fibroblasts: Epigenetic Repression of the Wnt Inhibitor SFRP1 in Rheumatoid Arthritis,” Annals of the Rheumatic Diseases 70, no. 8 (2011): 1482–1488.

[280] C. Miao, J. Chang, J. Dou, Y. Xiong, and G. Zhou, “DNA Hypermethylation of SFRP2 Influences the Pathology of Rheumatoid Arthritis Through the Canonical Wnt Signaling in Model Rats,” Autoimmunity 51, no. 7 (2018): 319–332.

[281] Y. Liu, Z. Sun, D. Xu, et al., “Hesperidin Derivative-11 Inhibits Fibroblast-Like Synoviocytes Proliferation by Activating Secreted Frizzled-related Protein 2 in Adjuvant Arthritis Rats,” European Journal of Pharmacology 794 (2017): 173–183.

[282] D. Elhaj Mahmoud, N. Sassi, and G. Drissi, “sFRP3 and DKK1 Regulate Fibroblast-Like Synoviocytes Markers and Wnt Elements Expression Depending on Cellular Context,” Immunological Investigations 46, no. 3 (2017): 314–328.

[283] C. G. Miao, C. Huang, Y. Huang, et al., “MeCP2 modulates the Canonical Wnt Pathway Activation by Targeting SFRP4 in Rheumatoid Arthritis Fibroblast-Like Synoviocytes in Rats,” Cell Signalling 25, no. 3 (2013): 598–608.

[284] Y. J. Kwon, S. W. Lee, Y. B. Park, S. K. Lee, and M. C. Park, “Secreted Frizzled-related Protein 5 Suppresses Inflammatory Response in Rheumatoid Arthritis Fibroblast-Like Synoviocytes Through Down-regulation of c-Jun N-terminal Kinase,” Rheumatology 53, no. 9 (2014): 1704–1711.

[285] R. Vitali, C. Mancini, V. Cesi, et al., “Slug (SNAI2) Down-regulation by RNA Interference Facilitates Apoptosis and Inhibits Invasive Growth in Neuroblastoma Preclinical Models,” Clinical Cancer Research 14, no. 14 (2008): 4622–4630.

[286] D. Jiang, S. Christ, and D. Correa-Gallegos, “Injury Triggers Fascia Fibroblast Collective Cell Migration to Drive Scar Formation Through N-cadherin,” Nature Communications 11, no. 1 (2020): 5653.

[287] D. Jiang and Y. Rinkevich, “Scars or Regeneration?-Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses,” International Journal of Molecular Sciences 21, no. 2 (2020): 617.

[288] P. Sklepkiewicz, T. Shiomi, R. Kaur, et al., “Loss of Secreted Frizzled-related Protein-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in human Cardiomyopathy,” Circ Heart Fail 8, no. 2 (2015): 362–372.

[289] D. E. Vatner, J. Zhang, X. Zhao, L. Yan, R. Kudej, and S. F. Vatner, “Secreted Frizzled Protein 3 Is a Novel Cardioprotective Mechanism Unique to the Clinically Relevant Fourth Window of Ischemic Preconditioning,” American Journal of Physiology. Heart and Circulatory Physiology 320, no. 2 (2021): H798–h804.

[290] E. De Langhe, C. Aznar-Lopez, V. De Vooght, J. A. Vanoirbeek, and F. P. Luyten, “Lories RJ. Secreted Frizzled Related Proteins Inhibit Fibrosis in Vitro but Appear Redundant in Vivo,” Fibrogenesis Tissue Repair 7 (2014): 14.

[291] L. Zareba, J. Szymanski, Z. Homoncik, and M. Czystowska-Kuzmicz, “EVs From BALF-Mediators of Inflammation and Potential Biomarkers in Lung Diseases,” International Journal of Molecular Sciences 22, no. 7 (2021): 3651.

[292] T. Tsukui, P. J. Wolters, and D. Sheppard, “Alveolar Fibroblast Lineage Orchestrates Lung Inflammation and Fibrosis,” Nature 631, no. 8021 (2024): 627–634.

[293] J. A. Moreno, E. Hamza, M. Guerrero-Hue, et al., “Non-Coding RNAs in Kidney Diseases: The Long and Short of Them,” International Journal of Molecular Sciences 22, no. 11 (2021): 6077.

[294] Y. Huang, P. Xu, F. Liao, et al., “Fat Mass and Obesity-associated Protein Inhibit the Pathology of Rheumatoid Arthritis Through the NSUN2/SFRP1/Wnt/β-catenin Signal Axis,” Journal of Pharmacy and Pharmacology 76, no. 3 (2024): 283–294.

[295] Z. Lv, H. Xu, X. Si, et al., “XAV-939 Inhibits Epithelial-mesenchymal Transformation in Pulmonary Fibrosis Induced by Crystalline Silica via the Wnt Signaling Pathway,” Environmental Toxicology 38, no. 2 (2023): 460–471.

[296] W. Liao, Y. Ang, A. C. L. Kee, et al., “Calcaratarin D, a Labdane Diterpenoid, Attenuates Bleomycin-induced Pulmonary Fibrosis by Blocking Wnt/β-catenin Signaling Pathway,” Pharmacological Research 216 (2025): 107756.

[297] T. Wang, L. T. Xu, P. P. Li, et al., “Physalis Calyx Seu Fructus Inhibited Pulmonary Fibrosis Through Regulating Wnt/β-catenin Signaling Pathway,” Phytomedicine 131 (2024):155797.

[298] Y. Yin, H. Hu, Y. Yang, and S. Wu, “Ginsenoside Rb1 Affects Mitochondrial Ca(2+) Transport and Inhibits Fat Deposition and Fibrosis by Regulating the Wnt Signaling Pathway to Treat Rotator Cuff Tears via Docking With SFRP1,” Molecular Medicine 30, no. 1 (2024): 240.

[299] H. He, B. Xu, P. Ge, et al., “The Effects of Taraxasterol on Liver Fibrosis Revealed by RNA Sequencing,” International Immunopharmacology 114 (2023): 109481.

[300] S. Chen, J. Suo, Y. Wang, et al., “Cordycepin Alleviates Diabetes Mellitus-associated Hepatic Fibrosis by Inhibiting SOX9-mediated Wnt/β-catenin Signal Axis,” Bioorganic Chemistry 153 (2024): 107812.

[301] Q. Q. Liu, J. Chen, T. Ma, W. Huang, and C. H. Lu, “DCDC2 inhibits Hepatic Stellate Cell Activation and Ameliorates CCl(4)-induced Liver Fibrosis by Suppressing Wnt/β-catenin Signaling,” Scientific Reports 14, no. 1 (2024): 9425.

[302] C. Cheng, Q. Wang, Y. Huang, et al., “Gandouling Inhibits Hepatic Fibrosis in Wilson's Disease Through Wnt-1/β-catenin Signaling Pathway,” Journal of Ethnopharmacology 311 (2023): 116445.

[303] J. Sun, Y. Jia, S. Chen, Y. Bian, H. Liang, and X. Du, “Adipose Mesenchymal Stem Cell-derived Extracellular Vesicles Alleviate Renal Fibrosis by Reducing Epithelial-mesenchymal Transition via the FOXS1/Wnt/β-catenin Signaling Pathway,” International Immunopharmacology 146 (2025): 113880.

[304] W. Zhong, Y. Jiang, H. Wang, et al., “Fibroblast Growth Factor 21 Alleviates Unilateral Ureteral Obstruction-induced Renal Fibrosis by Inhibiting Wnt/β-catenin Signaling Pathway,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1871, no. 2 (2024): 119620.

[305] J. Li, L. Shu, Q. Jiang, et al., “Oridonin Ameliorates Renal Fibrosis in Diabetic Nephropathy by Inhibiting the Wnt/β-catenin Signaling Pathway,” Renal Failure 46, no. 1 (2024): 2347462.

[306] H. M. Hassan, N. M. Alatawi, A. Bagalagel, et al., “Genistein Ameliorated Experimentally Induced Gastric Ulcer in Rats via Inhibiting Gastric Tissues Fibrosis by Modulating Wnt/β-catenin/TGF-β/PKB Pathway,” Redox Report: Communications in Free Radical Research 28, no. 1 (2023): 2218679.

[307] K. Kimura, T. Kanto, S. Shimoda, et al., “Safety, Tolerability, and Anti-fibrotic Efficacy of the CBP/β-catenin Inhibitor PRI-724 in Patients With hepatitis C and B Virus-induced Liver Cirrhosis: An Investigator-initiated, Open-label, Non-randomised, Multicentre, Phase 1/2a Study,” EBioMedicine 80 (2022): 104069.

[308] M. J. Jarrett, A. K. Houk, P. E. McCuistion, et al., “Wnt Signaling Mediates Pro-Fibrogenic Activity in Human Aortic Valve Interstitial Cells,” Annals of Thoracic Surgery 112, no. 2 (2021): 519–525.

[309] T. Liu, F. Gonzalez De Los Santos, M. Hirsch, Z. Wu, and S. H. Phan, “Noncanonical Wnt Signaling Promotes Myofibroblast Differentiation in Pulmonary Fibrosis,” American Journal of Respiratory Cell and Molecular Biology 65, no. 5: 489–499.

[310] S. Guan and J. Zhou, “Frizzled-7 Mediates TGF-β-induced Pulmonary Fibrosis by Transmitting Non-canonical Wnt Signaling,” Experimental Cell Research 359, no. 1 (2017): 226–234.

[311] K. Surendran, S. Schiavi, and K. A. Hruska, “Wnt-dependent Beta-catenin Signaling Is Activated After Unilateral Ureteral Obstruction, and Recombinant Secreted Frizzled-related Protein 4 Alters the Progression of Renal Fibrosis,” Journal of the American Society of Nephrology 16, no. 8 (2005): 2373–2384.

[312] W. He, C. Dai, Y. Li, G. Zeng, S. P. Monga, and Y. Liu, “Wnt/Beta-catenin Signaling Promotes Renal Interstitial Fibrosis,” Journal of the American Society of Nephrology: JASN 20, no. 4 (2009): 765–776.

[313] J. Liu, X. Zheng, C. Zhang, C. Zhang, and P. Bu, “Lcz696 Alleviates Myocardial Fibrosis after Myocardial Infarction through the sFRP-1/Wnt/β-Catenin Signaling Pathway,” Frontiers in pharmacology 12 (2021): 724147.

[314] D. E. Ingber, “Human Organs-on-chips for Disease Modelling, Drug Development and Personalized Medicine,” Nature Reviews Genetics 23, no. 8 (2022): 467–491.

[315] Z. X. Hong, S. T. Zhu, H. Li, et al., “Bioengineered Skin Organoids: From Development to Applications,” Mil Med Res 10, no. 1 (2023): 40.

[316] D. Correa-Gallegos, D. Jiang, S. Christ, et al., “Patch Repair of Deep Wounds by Mobilized Fascia,” Nature 576, no. 7786 (2019): 287–292.

[317] D. Correa-Gallegos, H. Ye, B. Dasgupta, et al., “CD201(+) fascia Progenitors Choreograph Injury Repair,” Nature 623, no. 7988 (2023): 792–802.

RIGHTS & PERMISSIONS

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.