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<p>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 CCl<sub>4</sub> (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<sup>+</sup>CD9<sup>+</sup> 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Heming Wu,
  • Xueqian Yan,
  • Lijun Kuang,
  • Yanfei Zhang,
  • Shuting Ye,
  • Rui Huang,
  • Yuehua Zhang,
  • Gaoliang Ouyang,
  • Tiantian Wu,
  • Fan Liu,
  • Yingfu Liu

摘要

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.