TGFBI promotes liver fibrosis through remodeling the profibrotic microenvironment by a positive feedback regulatory loop

  • Commun Biol. 2026 Feb 3;9(1):355. doi: 10.1038/s42003-026-09601-2.
Heming Wu  #  1 ,  Xueqian Yan  #  1 ,  Lijun Kuang  1 ,  Yanfei Zhang  2 ,  Shuting Ye  2 ,  Rui Huang  1 ,  Yuehua Zhang  3 ,  Gaoliang Ouyang  2 ,  Tiantian Wu  4 ,  Fan Liu  5 ,  Yingfu Liu  6
Affiliations
  • 1. Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China.
  • 2. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
  • 3. Laboratory Animal Center, Xiamen University, Xiamen, China.
  • 4. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China. [email protected].
  • 5. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • 6. Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China. [email protected].
  • # Contributed equally.
PMID: 41634371 DOI: 10.1038/s42003-026-09601-2
Abstract

Liver fibrosis is a major global health burden with limited treatment options. Transforming growth factor-beta-induced protein (TGFBI) is crucial in fibrotic diseases and tumors, however, its precise mechanism in liver fibrosis remains unclear. Here we show that TGFBI promotes liver fibrosis in male C57BL/6 mice. TGFBI is upregulated in fibrotic livers and derived from non-parenchymal cells. Genetic TGFBI deficiency alleviates liver fibrosis in both CCl4 (carbon tetrachloride) injection and bile duct ligation (BDL) models. Mechanistically, PDGFRβ is identified via RNA Sequencing as a key downstream molecule upregulated by TGFBI in hepatic stellate cells (HSCs) via the Integrin αvβ3-FAK-STAT3 pathway, promoting HSC proliferation and activation. Meanwhile, TGFBI increases PDGF-B expression in macrophages through the Integrin αvβ3-AKT-ERK pathway, driving their proliferation, migration and differentiation into the profibrotic TREM2+CD9+ subpopulation. Elevated PDGF-B reversely stimulates TGFBI production in macrophages, which creates a positive feedback loop. This TGFBI-mediated interaction between HSCs and macrophages remodels the profibrotic microenvironment to promote liver fibrosis, identifying a potential therapeutic target.

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