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Lying at the crossroad of TGF-\u03b2 and TLR signaling, TGF-\u03b2\u2013activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc and to investigate pharmacological TAK1 blockade using a potentially novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-\u03b21 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and it ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.<\/jats:p>","DOI":"10.1172\/jci.insight.165358","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T10:17:42Z","timestamp":1686565062000},"source":"Crossref","is-referenced-by-count":28,"title":["Pharmacological inhibition of TAK1 prevents and induces regression of experimental organ fibrosis"],"prefix":"10.1172","volume":"8","author":[{"given":"Swarna","family":"Bale","sequence":"first","affiliation":[{"name":"Michigan Scleroderma Program, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Verma","sequence":"additional","affiliation":[{"name":"Michigan Scleroderma Program, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharath","family":"Yalavarthi","sequence":"additional","affiliation":[{"name":"Michigan Scleroderma Program, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott Arthur","family":"Scarneo","sequence":"additional","affiliation":[{"name":"EydisBio Inc., Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Hughes","sequence":"additional","affiliation":[{"name":"EydisBio Inc., Durham, North Carolina, USA."},{"name":"Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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