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Updated: Jan 14, 2026

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TGF-β1 promotes collagen synthesis in systemic sclerosis via upregulating P4HA3

Zhaopeng Chen1, Yinru Lin1, Yayi Huang1

  • 1Department of Rheumatology and Immunology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.

Journal of Translational Autoimmunity
|October 23, 2025
PubMed
Abstract

Insights

Systemic sclerosis (SSc) fibrosis may be treated by inhibiting P4HA3, an enzyme upregulated by TGF-β1. This study identified P4HA3 as a key fibrotic gene in SSc, offering a potential therapeutic target.

Area of Science:

  • Immunology
  • Biochemistry
  • Genetics

Background:

  • Systemic sclerosis (SSc) is an autoimmune disease causing organ fibrosis and high mortality.
  • Current treatments for SSc fibrosis remain limited, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To identify a key fibrotic gene in Systemic sclerosis (SSc) and evaluate its potential as an antifibrotic therapeutic target.
  • To investigate the role of P4HA3 in SSc pathogenesis and its regulation by TGF-β1.

Main Methods:

  • Bioinformatics analysis of SSc patient data (GSE181549, GSE138669) including differential expression, PPI network, and GSEA.
  • Single-cell analysis, immunohistochemistry, and in vitro/in vivo experimental models using bleomycin and TGF-β1.

Main Results:

  • P4HA3 was identified as a key upregulated fibrotic gene in SSc, correlating with disease severity.
  • TGF-β1, secreted by immune cells, upregulates P4HA3 in fibroblasts, promoting collagen synthesis.
  • Inhibition of Collagen prolyl 4-hydroxylases (C-P4Hs), including P4HA3, ameliorated experimental fibrosis.

Conclusions:

  • P4HA3 is a critical mediator of fibrosis in Systemic sclerosis, driven by TGF-β1.
  • Inhibition of C-P4Hs represents a promising antifibrotic therapeutic strategy for SSc.
Keywords:
P4HA3Prolyl 4-hydroxylasesSFRP2SclerodermaSystemic sclerosis

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