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Selective JAK-1 inhibitor Upadacitinib and peptide PD29 modulate the JAK and TGF-β/Smad signaling pathways reducing

Ayşe Koçak1, Cemre Ural2, Zahide Cavdar2

  • 1Kütahya Health Sciences University, Faculty of Medicine, Medical Biochemistry Department, Kütahya, Türkiye.

Toxicology in Vitro : an International Journal Published in Association with BIBRA
|May 17, 2025
PubMed

Insights

Janus kinase (JAK) inhibitors like upadacitinib and PD29 peptide show antifibrotic and anti-inflammatory effects in systemic sclerosis models. Combination therapy effectively reduced fibrosis and inflammation by inhibiting key signaling pathways.

Area of Science:

  • Immunology
  • Pharmacology
  • Fibrosis Research

Background:

  • Systemic sclerosis (SSc) involves dermal thickening, inflammation, and fibrosis, often leading to fatal complications like pulmonary arterial hypertension.
  • The TGF-β/Smad signaling pathway is implicated in SSc pathogenesis.
  • Current treatments for SSc fibrosis are limited.

Purpose of the Study:

  • To investigate the antifibrotic and anti-inflammatory effects of upadacitinib (a JAK1 inhibitor) and PD29 peptide in systemic sclerosis.
  • To evaluate the efficacy of monotherapy versus combination therapy with upadacitinib and PD29.
  • To elucidate the underlying molecular mechanisms, particularly the TGF-β1/Smad signaling pathway.

Main Methods:

  • A bleomycin-induced SSc mouse model and primary human lung fibroblasts were used.
  • Upadacitinib and PD29 peptide were administered individually and in combination.
  • Gene and protein expression of fibrotic markers (α-SMA, collagen-1) and signaling molecules (JAK1, TGF-β1, Smad2) were analyzed.
  • Levels of inflammatory cytokines (IL-6, TNF-α) were measured.

Main Results:

  • Both upadacitinib and PD29 significantly reduced dermal thickening, myofibroblast transdifferentiation, and collagen deposition in SSc models.
  • Treatment downregulated key fibrotic markers (α-SMA, JAK1, TGF-β1, Smad2, collagen-1) at gene and protein levels.
  • Systemic inflammatory cytokines (IL-6, TNF-α) were significantly reduced, with combination therapy showing superior efficacy.

Conclusions:

  • Upadacitinib and PD29 peptide demonstrate potent antifibrotic and anti-inflammatory effects in SSc.
  • Therapeutic benefits are mediated through the suppression of TGF-β1-induced Smad2/3 signaling via JAK1 inhibition.
  • JAK inhibitors and PD29 peptide are promising candidates for treating fibrosis in systemic sclerosis.
Keywords:
FibrosisJAK-STAT pathwayPD29 peptideSystemic sclerosisTGF-β/Smad signalingUpadacitinib

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