Trinh-Minh, ThuongThuongTrinh-MinhChen, Chih-WeiChih-WeiChenTran Manh, CuongCuongTran ManhLi, Yi-NanYi-NanLiZhu, HonglinHonglinZhuZhou, XiangXiangZhouChakraborty, DebomitaDebomitaChakrabortyZhang, YunYunZhangRauber, SimonSimonRauberDees, ClaraClaraDeesNENG-YU LINKah, DelfDelfKahGerum, RichardRichardGerumBergmann, ChristinaChristinaBergmannKreuter, AlexanderAlexanderKreuterReuter, ChristianeChristianeReuterGroeber-Becker, FlorianFlorianGroeber-BeckerEckes, BeateBeateEckesDistler, OliverOliverDistlerFabry, BenBenFabryRamming, AndreasAndreasRammingSchambony, AlexandraAlexandraSchambonySchett, GeorgGeorgSchettDistler, Jörg HwJörg HwDistler2024-12-252024-12-252024-03-26https://scholars.lib.ntu.edu.tw/handle/123456789/724371Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-β in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-β. The activation of latent TGF-β requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-β, rebalanced TGF-β signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-β in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.enDermatologyFibrosisPulmonology[SDGs]SDG3journal article10.1172/JCI15988438747285