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.
Data availability
The data generated in this study have been made publicly available to ensure verifiability. The RNA sequencing data are stored in the Science Data Bank of the Chinese Academy of Sciences (ScienceDB) and can be accessed publicly through the persistent identifier (DOI: 10.57760/sciencedb.35038). The quantitative source data of all figures in the text can be found in Supplementary Data 1. The untrimmed original blot images are included in Supplementary Fig. 16 of the supplementary information file. If there are any other material requirements, you can contact the corresponding author for assistance.
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Acknowledgements
This research was supported by the National Natural Science Foundation of China (82370623, 82571812, 82170600, 82070607, and 82273416) and the Natural Science Foundation of Fujian Province of China (2022J01015).
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H.W. designed and conducted the experiments, analyzed and interpreted the data, and drafted the manuscript. X.Y. and Yan.Z2. conducted the experiments and collected the data. L.K. and Yue.Z3. conducted the experiments. R.H. and S.Y. provided technical support. G.O. inputs critical intellectual property. T.W. analyzed and interpreted the data. Fan L. and Y.L. designed the study, analyzed and interpreted the data, critically revised the manuscript, obtained funding, and supervised the study.
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Wu, H., Yan, X., Kuang, L. et al. TGFBI promotes liver fibrosis through remodeling the profibrotic microenvironment by a positive feedback regulatory loop. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09601-2
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DOI: https://doi.org/10.1038/s42003-026-09601-2
