The impact of hypoxia and glycolysis on liver fibrosis

BACKGROUND AND METHODS: Hypoxia, glycolysis, and lactylation are key processes in liver fibrosis (LF) and hepatocarcinogenesis, yet the role of hypoxia-, glycolysis-, and lactylation-related genes (HGLRGs) in LF is poorly defined. Here, we systematically analyzed transcriptomic data from LF samples to identify differentially expressed HGLRGs, validate by single-cell transcriptomics, construct co-expression networks, evaluate their biological functions, diagnostic performance, immune relevance, and explore potential therapeutic agents. RESULTS: Seven HGLRGs-CHST4, FABP5, GPC3, SOX9, SRPX, IFI16, and ISG20-were significantly upregulated in LF and demonstrated strong diagnostic value. FABP5 and ISG20 were consistently elevated in activated stellate cells and human cirrhotic livers. Enrichment analyses indicated that these genes modulate metabolic pathways and drive immune-mediated fibrotic responses. Immune profiling revealed that ISG20 expression inversely correlated with resting NK cell infiltration, and SOX9 with M2 macrophage infiltration. Molecular docking identified seven FDA-approved drugs, including aspirin, Methylene blue, tamoxifen, vorinostat, valproic acid, rosiglitazone and acetaminophen, as potential HGLRG-targeting agents. CONCLUSION: HGLRGs are aberrantly upregulated and actively contribute to LF progression through metabolic dysregulation and immune remodeling. FABP5 and ISG20 represents promising biomarkers and therapeutic target. This study providing novel diagnostic markers, drug repurposing opportunities, and strategies for improved clinical management of liver cirrhosis.