Antifibrotic therapeutic strategies in systemic sclerosis: Critical role of the Wnt/β-catenin and TGF-β signal transduction pathways as potential targets

Leyla Bagheri; Mohammad Javanbakht; Sheida Malekian; Bahareh Heshmat Ghahderijani; Sadra Taghipour; Fatemeh Davari Tanha; Mohammadhosein Ranjkesh; Luca Cegolon; Shi Zhao

doi:10.1016/j.ejphar.2025.177607

Antifibrotic therapeutic strategies in systemic sclerosis: Critical role of the Wnt/β-catenin and TGF-β signal transduction pathways as potential targets

Eur J Pharmacol. 2025 Jul 15:999:177607. doi: 10.1016/j.ejphar.2025.177607. Epub 2025 Apr 8.

Authors

Leyla Bagheri¹, Mohammad Javanbakht², Sheida Malekian³, Bahareh Heshmat Ghahderijani⁴, Sadra Taghipour⁵, Fatemeh Davari Tanha⁶, Mohammadhosein Ranjkesh⁷, Luca Cegolon⁸, Shi Zhao⁹

Affiliations

¹ Department of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: l.bagheri@sbmu.ac.ir.
² Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
³ Department of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁴ Tehran University of Medical Sciences, Tehran, Iran.
⁵ Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
⁶ Department of Infertility, Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran.
⁷ Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran.
⁸ Department of Medical, Surgical & Health Sciences, University of Trieste, 34128, Trieste, Italy; Public Health Unit, University Health Agency Giuliano-Isontina (ASUGI), 34148, Trieste, Italy.
⁹ School of Public Health, Tianjin Medical University, Tianjin, 300070, China.

PMID: 40209848
DOI: 10.1016/j.ejphar.2025.177607

Abstract

Systemic sclerosis (SSc) is a prototypic fibrosing disorder characterized by widespread fibrosis and immune dysregulation. Current evidence highlights the intricate cross-talk between the canonical Wnt/β-catenin signaling pathway and transforming growth factor-beta (TGF-β) signaling, both of which play fundamental roles in the pathogenesis of fibrosis. This review aims to elucidate the central role of the Wnt/β-catenin-TGF-β pathway and TGF-β signal transduction pathway in fibrotic diseases, focusing on SSc. We summarized evidence from cellular biology studies, animal model investigations and clinical observations to provide a comprehensive view of the mechanisms causing pathological fibrosis. In addition, we explore the possibilities of antifibrotic therapeutic strategies against Wnt/β-catenin-TGF-β signaling to counteract fibrosis, delineating approaches for treatment of SSc patients by targeting these interconnected signaling pathways.

Keywords: Cellular biology; Fibrotic processes; Systemic sclerosis; TGF-β signal transduction pathway.

Publication types

Review

MeSH terms

Animals
Antifibrotic Agents* / pharmacology
Antifibrotic Agents* / therapeutic use
Fibrosis
Humans
Molecular Targeted Therapy
Scleroderma, Systemic* / drug therapy
Scleroderma, Systemic* / metabolism
Scleroderma, Systemic* / pathology
Signal Transduction
Transforming Growth Factor beta* / metabolism
Wnt Signaling Pathway* / drug effects
beta Catenin* / metabolism

Substances

Transforming Growth Factor beta
Antifibrotic Agents
beta Catenin