Wu Hua-Yue, Han Lu, Ran Tao, Sun Yong, Zhang Qing-Xiu, Huang Tao, Zou Gao-Liang, Zhang Ya, Zhou Yu-Mei, Lin Guo-Yuan, Chen Shao-Jie, Wang Jing-Lin, Pan Chen, Lu Fan, Pu Hong-Fei, Zhao Xue-Ke
Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.
Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China.
World J Gastroenterol. 2025 Jul 28;31(28):107361. doi: 10.3748/wjg.v31.i28.107361.
Inhibiting hepatic stellate cell (HSC) activation is a key therapeutic strategy in liver fibrosis (LF). During activation, aerobic glycolysis is upregulated to meet increased energy demands. Although focal adhesion kinase (FAK) has been implicated in regulating HSC glycolysis, its precise role in activation remains unclear.
To investigate the effects of FAK and fructose-1, 6-bisphosphatase 1 (FBP1) on LF through the modulation of aerobic glycolysis in HSCs.
Eighteen mice were randomly assigned to three groups: Control, carbon tetrachloride (CCl₄)-induced LF, and CCl₄ with FAK inhibitor treatment. Liver tissues were analyzed using transcriptomic and proteomic sequencing. Differential gene expression, Mfuzz clustering, and protein interaction network analyses identified key regulatory factors. Immunohistochemistry (IHC) and Western blot (WB) analysis were used to assess FAK and FBP1 expression, along with glycolysis-related enzymes. The migratory behavior of HSCs was evaluated using Transwell migration and scratch assays.
Transcriptomic and proteomic analyses revealed significantly reduced FBP1 expression in CCl₄-induced fibrosis, which was restored upon FAK inhibition. Histological staining (hematoxylin and eosin, Masson's trichrome, Sirius red) confirmed reduced fibrosis following FAK inhibition. WB analysis demonstrated suppression of glycolysis-related enzymes. In LX-2 cells, FAK inhibition attenuated HSC activation and glycolysis while upregulating FBP1. Exogenous recombinant FBP1 inhibited HSC activation and glycolysis. Transwell and scratch assays showed that FBP1 significantly impaired HSC migration. In addition, WB and IHC analyses confirmed lower FBP1 expression in fibrotic liver tissues from patients compared to healthy controls.
FAK inhibitors and increased FBP1 expression inhibit aerobic glycolysis in HSCs, thereby improving LF. Thus, FAK and FBP1 may be potential targets for LF treatment.
抑制肝星状细胞（HSC）激活是肝纤维化（LF）治疗的关键策略。在激活过程中，有氧糖酵解上调以满足增加的能量需求。尽管粘着斑激酶（FAK）与调节HSC糖酵解有关，但其在激活中的精确作用仍不清楚。
通过调节HSCs中的有氧糖酵解来研究FAK和果糖-1,6-二磷酸酶1（FBP1）对LF的影响。
18只小鼠随机分为三组：对照组、四氯化碳（CCl₄）诱导的LF组和CCl₄加FAK抑制剂治疗组。使用转录组学和蛋白质组学测序分析肝组织。差异基因表达、Mfuzz聚类和蛋白质相互作用网络分析确定关键调节因子。免疫组织化学（IHC）和蛋白质印迹（WB）分析用于评估FAK和FBP1表达以及糖酵解相关酶。使用Transwell迁移和划痕试验评估HSCs的迁移行为。
转录组学和蛋白质组学分析显示，CCl₄诱导的纤维化中FBP1表达显著降低，FAK抑制后恢复。组织学染色（苏木精和伊红、Masson三色染色、天狼星红）证实FAK抑制后纤维化减轻。WB分析显示糖酵解相关酶受到抑制。在LX-2细胞中，FAK抑制减弱了HSC激活和糖酵解，同时上调了FBP1。外源性重组FBP1抑制了HSC激活和糖酵解。Transwell和划痕试验表明FBP1显著损害了HSC迁移。此外，WB和IHC分析证实，与健康对照相比，患者纤维化肝组织中FBP1表达较低。
FAK抑制剂和FBP1表达增加可抑制HSCs中的有氧糖酵解，从而改善LF。因此，FAK和FBP1可能是LF治疗的潜在靶点。
