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Cited by 0Liver physiology and pathologyDrug-Induced Hepatotoxicity and ProtectionFibroblast Growth Factor Research

Metformin Drives Hepatocyte Molecular Reprogramming Through a Fibroblast Growth Factor 1–Fibroblast Growth Factor Receptor 4–T-Box Transcription Factor 3 Axis in Cholestasis

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Liang, Yingyu, Peng, Yue, Song, Zhejun, Bao, Xiaowen, Zhang, Wenxia, Lu, Qingyu, Lian, Haoran, Ye, Yongqin +5 more·2026·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2026.101909
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Abstract

BACKGROUND & AIMS: Cholestatic liver fibrosis involves a pathological shift from hepatocyte to cholangiocyte molecular signatures. Metformin has hepatoprotective effects, but its impact on this shift remains unclear. We investigated whether metformin reverses this pathological program and elucidated the underlying mechanisms. METHODS: We employed purified hepatocyte organoids derived from bile duct ligation (BDL) and Mdr2-/- mouse models of cholestasis, as well as patient-derived organoids (PDOs) from patients. Transcriptomic and functional analyses were performed to assess metformin-induced molecular changes. Gain- and loss-of-function studies, including hepatocyte-specific Fgf1 knockout mice and FGFR4 inhibition, were used to dissect the signaling axis. RESULTS: Metformin reversed the pathological gene expression profile in liver organoids, restoring hepatocyte-associated transcripts while suppressing cholangiocyte-associated, and concomitantly elevated TBX3 expression in both BDL and Mdr2-/- models. This molecular effect correlated with upregulation of the FGF1/FGFR4 signaling axis. Gain- and loss-of-function studies confirmed that FGF1 is sufficient to drive TBX3 expression and promote the hepatocyte-associated gene program, whereas FGFR4 inhibition partially suppressed these effects and exacerbated fibrosis. Strikingly, the pro-hepatocyte molecular state induced by either metformin or FGF1 in vivo was retained in ex vivo organoids, indicating durable, cell-intrinsic reprogramming. Genetic ablation of hepatocyte-derived Fgf1 partially abolished metformin's ability to induce TBX3 and the hepatocyte gene program, establishing a necessary and autonomous role for FGF1. Crucially, in PDOs, both metformin and FGF1 upregulated TBX3 and promoted a hepatocyte molecular program in an FGFR4-dependent manner. CONCLUSIONS: The metformin-FGF1/FGFR4-TBX3 axis licenses durable molecular reprogramming favoring a functional hepatocyte state, providing a mechanistic foundation for promoting liver repair in cholestasis.

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Crossref · 10.1016/j.jcmgh.2026.101909

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Authors
Liang, Y., Peng, Y., Song, Z., Bao, X., Zhang, W., Lu, Q., Lian, H., Ye, Y., Wang, W., Chen, Y., Hang Lui, V. C., Hang Tam, P. K., & Chen, Y.
Affiliations
Macau University of Science and Technology (MO)
ORCID
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2026-10
Pages
101909
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2026.101909
OpenAlex
W7215028947
Semantic Scholar
181623089dfa10ca1bda81bec14251d22f55ef71
Cited by
0
References
29
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Keywords
metformin, cholestasis, FGF1, FGFR4, TBX3, hepatocyte differentiation, drug repurposing

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