Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis
Abstract 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 live...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-88538-8 |
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| author | Tao Huang Ming-Yu Zhou Gao-Liang Zou Rui-Han Hu Lu Han Qing-Xiu Zhang Xue-Ke Zhao |
| author_facet | Tao Huang Ming-Yu Zhou Gao-Liang Zou Rui-Han Hu Lu Han Qing-Xiu Zhang Xue-Ke Zhao |
| author_sort | Tao Huang |
| collection | DOAJ |
| description | Abstract 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. 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. 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. FAK promotes aerobic glycolysis in LX-2 cells through the cyclin D1/c-Myc/MCT-1 pathway, thereby increasing liver fibrosis. |
| format | Article |
| id | doaj-art-c7e503798c164e689611a43ebed7d7cb |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-c7e503798c164e689611a43ebed7d7cb2025-02-09T12:32:09ZengNature PortfolioScientific Reports2045-23222025-02-0115111310.1038/s41598-025-88538-8Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosisTao Huang0Ming-Yu Zhou1Gao-Liang Zou2Rui-Han Hu3Lu Han4Qing-Xiu Zhang5Xue-Ke Zhao6Department of Infectious Disease, the Affiliated Hospital of Guizhou Medical UniversityDepartment of Infectious Disease, the Affiliated Hospital of Guizhou Medical UniversityDepartment of Infectious Disease, the Affiliated Hospital of Guizhou Medical UniversityDepartment of Cardiology, Guiqian International General HospitalDepartment of Comprehensive Ward, the Affiliated Hospital of Guizhou Medical UniversityDepartment of Infectious Disease, the Affiliated Hospital of Guizhou Medical UniversityDepartment of Infectious Disease, the Affiliated Hospital of Guizhou Medical UniversityAbstract 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. 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. 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. FAK promotes aerobic glycolysis in LX-2 cells through the cyclin D1/c-Myc/MCT-1 pathway, thereby increasing liver fibrosis.https://doi.org/10.1038/s41598-025-88538-8Focal adhesion kinaseLiver fibrosisAerobic glycolysisMonocarboxylate transporter 1Multiomics analysis |
| spellingShingle | Tao Huang Ming-Yu Zhou Gao-Liang Zou Rui-Han Hu Lu Han Qing-Xiu Zhang Xue-Ke Zhao Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis Scientific Reports Focal adhesion kinase Liver fibrosis Aerobic glycolysis Monocarboxylate transporter 1 Multiomics analysis |
| title | Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis |
| title_full | Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis |
| title_fullStr | Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis |
| title_full_unstemmed | Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis |
| title_short | Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis |
| title_sort | focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin d1 c myc mct 1 pathway to induce liver fibrosis |
| topic | Focal adhesion kinase Liver fibrosis Aerobic glycolysis Monocarboxylate transporter 1 Multiomics analysis |
| url | https://doi.org/10.1038/s41598-025-88538-8 |
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