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However, the role of testicular receptor 4 (TR4; or Nr2c2) in fibroblast activation and rheumatologic diseases has not yet been investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>TR4 expression in human skin and experimental fibrosis were determined by immunofluorescence staining and Western blot. RNA sequencing (RNAseq) was performed in transforming growth factor \u03b2 (TGF\u03b2)\u2010stimulated fibroblasts with or without TR4 knockdown by small interfering RNA. Myofibroblast differentiation was assessed by \u03b1\u2010smooth muscle actin and extracellular matrix staining, and Rho\u2010associated protein kinase (ROCK) activity was assessed by enzyme\u2010linked immunosorbent assay. Fibroblast\u2010specific Tr4 knockout mice were subjected to constitutively active TGF\u03b2 receptor type I\u2013, bleomycin\u2010, and chronic graft\u2010versus\u2010host disease\u2013induced dermal fibrosis and bleomycin\u2010induced pulmonary fibrosis. Precision\u2010cut skin slices (PCSSs) from patients with systemic sclerosis (SSc) were used for TR4 knockdown studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TR4 was up\u2010regulated in fibroblasts in the skin of patients with SSc and in murine models of SSc. TGF\u03b2 induced TR4 in fibroblasts in an SMAD3\u2010dependent manner. Knockdown of TR4 prevented fibroblast\u2010to\u2010myofibroblast transition, and fibroblast\u2010specific knockout of Tr4 ameliorated experimental murine skin and pulmonary fibrosis. RNAseq and functional experiments identified the profibrotic effects of TR4 were dependent on G protein subunit alpha 12\u2013 and ROCK\u2010associated cytoskeletal remodeling. PCSSs confirmed that TR4 regulates ROCK signaling and the expression of profibrotic genes in SSc skin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TR4 is up\u2010regulated in SSc in a TGF\u03b2\u2010dependent manner and drives fibroblast activation. Inhibition of TR4 prevents ROCK activation and fibroblast\u2010to\u2010myofibroblast transition and ameliorates dermal and pulmonary fibrosis, highlighting TR4 as a potential therapeutic target in SSc and related diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70228","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:49:17Z","timestamp":1779972557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Nuclear Receptor Testicular Receptor 4 Orchestrates Cytoskeletal Organization in a G Protein Subunit Alpha 12\/Rho\u2010Associated Protein Kinase\u2013Dependent Manner to Promote Myofibroblast Differentiation and Tissue Fibrosis in Systemic Sclerosis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4016-0081","authenticated-orcid":false,"given":"Yun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of 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