Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis

Nat Commun. 2017 Oct 24;8(1):1130. doi: 10.1038/s41467-017-01236-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aminosalicylic Acids / chemistry
  • Animals
  • Benzenesulfonates / chemistry
  • Biopsy
  • Bleomycin / chemistry
  • Collagen / chemistry
  • Enzyme Activation
  • Female
  • Fibroblasts / metabolism
  • Fibrosis / metabolism*
  • Humans
  • Inflammation
  • Male
  • Mice
  • Microscopy, Confocal
  • Middle Aged
  • Phosphorylation
  • Receptors, Transforming Growth Factor beta / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Scleroderma, Systemic / metabolism*
  • Signal Transduction / physiology
  • Skin / metabolism
  • Transforming Growth Factor beta / metabolism
  • Young Adult


  • Aminosalicylic Acids
  • Benzenesulfonates
  • NSC 74859
  • Receptors, Transforming Growth Factor beta
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Transforming Growth Factor beta
  • Bleomycin
  • Collagen