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粘着斑激酶通过细胞周期蛋白D1/c-Myc/单羧酸转运蛋白1途径促进肝星状细胞的有氧糖酵解，从而诱导肝纤维化。

Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis.

作者信息

Huang Tao, Zhou Ming-Yu, Zou Gao-Liang, Hu Rui-Han, Han Lu, Zhang Qing-Xiu, Zhao Xue-Ke

机构信息

Department of Infectious Disease, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China.

Department of Cardiology, Guiqian International General Hospital, Guiyang, Guizhou Province, China.

出版信息

Sci Rep. 2025 Feb 7;15(1):4552. doi: 10.1038/s41598-025-88538-8.

DOI:10.1038/s41598-025-88538-8
PMID:39915293
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11802747/
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 (CCl)-induced liver fibrosis was performed to identify the downstream FAK signaling pathway. The effect of the FAK inhibitor PF562271 on CCl-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.

摘要

肝星状细胞（HSCs）在肝纤维化过程中会转分化为肌成纤维细胞，并表现出糖酵解增加。磷酸化的粘着斑激酶（FAK）（pY397-FAK）促进肝星状细胞中单羧酸转运蛋白1（MCT-1）的表达，以增加有氧糖酵解并导致肝纤维化。对四氯化碳（CCl）诱导的肝纤维化C57BL/6小鼠进行了联合多组学分析，以确定下游的FAK信号通路。通过肝组织免疫荧光研究了FAK抑制剂PF562271对CCl诱导的肝纤维化的影响。在体外评估了转化生长因子β1（TGF-β1）刺激激活或PF562271抑制后LX-2细胞的迁移、增殖和有氧糖酵解。对成功构建的CCl4诱导的肝纤维化小鼠模型进行了多组学分析。FAK和细胞周期蛋白D1在CCl4诱导的肝纤维化小鼠中显著富集。在体内，CCl4诱导的肝纤维化小鼠中MCT-1和α平滑肌肌动蛋白（α-SMA）水平升高，PF562271治疗后MCT-1和α-SMA表达降低。在体外，PF562271减轻了TGF-β1诱导的LX-2激活。PF562271干预后，LX-2细胞的迁移、增殖和有氧糖酵解减弱。FAK通过细胞周期蛋白D1/c-Myc/MCT-1途径促进LX-2细胞的有氧糖酵解，从而增加肝纤维化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/c3ba03e4e4b8/41598_2025_88538_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/40010aaeb972/41598_2025_88538_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/20eacb379ad2/41598_2025_88538_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/e20226caf881/41598_2025_88538_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/185c5d996ba0/41598_2025_88538_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/e073b36ad9c9/41598_2025_88538_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/c3ba03e4e4b8/41598_2025_88538_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/40010aaeb972/41598_2025_88538_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/20eacb379ad2/41598_2025_88538_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/e20226caf881/41598_2025_88538_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/185c5d996ba0/41598_2025_88538_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/e073b36ad9c9/41598_2025_88538_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce72/11802747/c3ba03e4e4b8/41598_2025_88538_Fig6_HTML.jpg

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