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Dermatomyositis is characterized by TYK2-dependent STAT3 activation

M Fornaro1, S Del Vescovo1, F Cacciapaglia2,3

  • 1Unit of Rheumatology, Department of Precision and Regenerative Medicine, Area Jonica (DiMePRe-J), University of Bari, Bari, Italy.

Clinical and Experimental Immunology
|July 8, 2026
PubMed

Insights

Dermatomyositis involves Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation. This study found TYK2 inhibition selectively reduced STAT3 activation in dermatomyositis patients, suggesting TYK2 as a therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Dermatomyositis (DM) pathogenesis involves cytokine pathways and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) axis.
  • The specific roles of individual JAK family members in DM remain incompletely understood.
  • Understanding JAK/STAT pathway contributions is crucial for developing targeted therapies for autoimmune diseases.

Purpose of the Study:

  • To investigate the contribution of individual Janus kinase (JAK) family members to signal transducer and activator of transcription 3 (STAT3) activation in dermatomyositis (DM).
  • To compare JAK/STAT pathway activation patterns in DM with those in rheumatoid arthritis (RA), systemic sclerosis (SSc), and healthy donors (HD).
  • To identify potential therapeutic targets within the JAK family for DM treatment.

Main Methods:

  • Peripheral blood mononuclear cells (PBMCs) were isolated from patients with active DM, RA, SSc, and HDs.
  • Phosphorylated STAT3 (pSTAT3) levels were measured using flow cytometry in CD4+ and CD14+ cells.
  • Selective inhibition of JAK1, JAK2, JAK3, and TYK2 was performed using specific inhibitors (abrocitinib, gandotinib, decernotinib, deucravacitinib) to assess their impact on pSTAT3.

Main Results:

  • Patients with active DM exhibited significantly higher basal pSTAT3 levels in CD4+ cells compared to HDs and SSc patients.
  • DM patients showed elevated pSTAT3 in CD14+ cells compared to HDs.
  • Selective TYK2 inhibition, but not other JAK inhibitors, significantly reduced pSTAT3 levels in both CD4+ and CD14+ cells in DM patients, unlike in RA, SSc, or HDs.

Conclusions:

  • A distinct pattern of TYK2-dependent STAT3 activation is identified in circulating immune cells of dermatomyositis patients.
  • This finding differentiates DM from other autoimmune conditions like RA and SSc.
  • TYK2 emerges as a potential targeted therapeutic strategy for managing dermatomyositis.
Keywords:
JAK inhibitorsJAK/STAT pathwaydermatomyositis

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