This study examined the role of the nuclear receptor TR4 (Nr2c2) in fibroblast activation and fibrosis in systemic sclerosis (SSc), using human SSc skin, precision-cut skin slices, and multiple murine fibrosis models (bleomycin, constitutively active TGFβRI, and chronic graft-versus-host disease) with fibroblast-specific Tr4 knockout.
TR4 was upregulated in SSc fibroblasts via TGFβ/SMAD3 signaling; fibroblast-specific Tr4 knockout ameliorated dermal and pulmonary fibrosis in all murine models tested. Mechanistically, TR4 drove myofibroblast differentiation through Gα12/ROCK-dependent cytoskeletal remodeling, and TR4 knockdown in SSc precision-cut skin slices reduced ROCK activity and profibrotic gene expression.
All intervention data are preclinical (murine knockout models and ex vivo human tissue slices); no clinical trial data are available. Study does not characterize potential off-target effects of TR4 inhibition in non-fibroblast cell types. The precise transcriptional targets through which TR4 activates Gα12 remain incompletely defined.
TR4 is not yet a clinically actionable target, but preclinical evidence positions it as a promising therapeutic candidate in SSc-related fibrosis. Clinicians should watch for TR4/ROCK pathway inhibitors entering early-phase trials in SSc and related fibrosing diseases.
