Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis
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Abstract
Abstract Background Hepatic stellate cells (HSCs) transdifferentiate into myofibroblasts during liver fibrosis and exhibit increased glycolysis. Phosphorylated focal adhesion kinase (FAK) (pY397-FAK) promotes monocarboxylate transporter 1 (MCT-1) expression in HSCs to increase aerobic glycolysis and cause liver fibrosis. Methods A combined multiomics analysis of C57BL/6 mice with tetrachloromethane (CCl4)-induced liver fibrosis was performed to identify the downstream FAK signaling pathway. The effect of the FAK inhibitor PF562271 on CCl4-induced liver fibrosis was explored by immunofluorescence of liver tissues. The migration, proliferation and aerobic glycolysis of LX-2 cells after stimulation and activation by transforming growth factor beta-1 (TGF-β1) or suppression by PF562271 was assessed in vitro. Results Multiomics analysis of a successfully generated CCl4-induced liver fibrosis mouse model was performed. FAK and cyclin D1 were significantly enriched in mice with CCl4-induced liver fibrosis. In vivo, the MCT-1 and alpha smooth muscle actin (α-SMA) levels were increased in mice with CCl4-induced liver fibrosis, and MCT-1 and α-SMA expression decreased after PF562271 treatment. In vitro, PF562271 alleviated TGF-β1-induced LX-2 activation. LX-2 cells showed diminished migration, proliferation, and aerobic glycolysis after PF562271 intervention. Conclusion FAK promotes aerobic glycolysis in LX-2 cells through the cyclin D1/c-Myc/MCT-1 pathway, thereby increasing liver fibrosis.
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- Authors
- Huang, T., Zhou, M.-Y., Zou, G.-L., Hu, R.-H., Han, L., Zhang, Q.-X., & Zhao, X.-K.
- Affiliations
- Affiliated Hospital of Guizhou Medical University (CN)
- Venue
- Scientific Reports
- Published
- 2025-02-07
- Volume
- 15
- Issue
- 1
- Pages
- 4552-4552
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC11802747
- OpenAlex
- W4407205504
- Cited by
- 14
- References
- 6
- Citations by year
- 2026: 7 · 2025: 7
- FWCI
- 7.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (82260129, 82060116)
- Guizhou Medical University
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- focal adhesion kinase, aerobic glycolysis, hepatic stellate cells, liver fibrosis, cyclin D1, c-Myc, MCT1, TGF-β1, alpha-smooth muscle actin, CCl4-induced liver fibrosis, LX-2 cells, FAK inhibitors
- MeSH terms
- Monocarboxylate Transport Protein 1, Animals, Carbon Tetrachloride, Cell Line, Cell Movement, Disease Models, Animal, Glycolysis, Humans, Liver Cirrhosis, Male, Mice, Inbred C57BL, Signal Transduction, Proto-Oncogene Proteins c-myc, Cyclin D1, Monocarboxylic Acid Transporters, Symporters, Cell Proliferation, Mice, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1, Hepatic Stellate Cells
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