Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.

Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology University Hospital Zurich Zurich 8091 Switzerland

Department of Internal Medicine 3 Rheumatology and Immunology Friedrich Alexander University Erlangen Nürnberg and University Hospital Erlangen Erlangen 91054 Germany

Department of Orthopaedic Trauma Surgery University Hospital Erlangen Friedrich Alexander University of Erlangen Nürnberg Erlangen 91054 Germany

Department of Plastic and Hand Surgery and Laboratory for Tissue Engineering and Regenerative Medicine University Hospital of Erlangen Friedrich Alexander University of Erlangen Nürnberg Erlangen 91054 Germany

Institute of Rheumatology and Department of Rheumatology 1st Faculty of Medicine Charles University Prague 120 00 Czech Republic

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Nat Rev Rheumatol. 2017 Nov 21;13(12):693. doi: 10.1038/nrrheum.2017.190. PubMed

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Nat Commun. 2021 Dec 8;12(1):7259. doi: 10.1038/s41467-021-27450-x. PubMed

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Nitro-Oleic Acid Inhibits Stemness Maintenance and Enhances Neural Differentiation of Mouse Embryonic Stem Cells via STAT3 Signaling