FABP5 regulates an immunosuppressive microenvironment in hepatocellular carcinoma through the NF-κB/PD-L1 axis

Background Fatty acid binding protein 5 (FABP5) contributes to lipid metabolism and inflammation, but, its immunoregulatory role in hepatocellular carcinoma (HCC) is unclear. Considering the strong metabolic–immune interplay in HCC, elucidating how FABP5 shapes the tumor immune microenvironment may uncover new therapeutic targets. Methods TCGA, CCLE and single-cell RNA-seq datasets were employed to characterize FABP5 expression and clinical relevance. FABP5 knockdown was performed to assess effects on HCC cell proliferation. Immune infiltration, immune checkpoint profiles, TIDE scores and enrichment of immune-related pathways were analyzed. Differentially expressed genes underwent GO and KEGG pathway enrichment analyses. Protein–protein docking, molecular dynamics (MD) simulations and in vitro assays were conducted to explore the regulatory role of FABP5 in the NF-κB/PD-L1 axis. Drug screening, molecular docking and duplicate MD simulations were carried out to identify potential FABP5-targeting compounds. Results FABP5 was significantly upregulated in HCC and predicted worse survival, serving as an independent prognostic factor. Single-cell analysis identified predominant FABP5 expression in fibroblasts and macrophages. FABP5 knockdown suppressed cell proliferation, colony formation, DNA synthesis and migration, accompanied by decreased expression of epithelial–mesenchymal transition (EMT) markers. FABP5-high tumors exhibited increased immune infiltration but raised immune checkpoint levels and higher TIDE scores, indicative of an immunosuppressive microenvironment. FABP5 correlated positively with NF-κB pathway genes and molecular docking predicted stable complexes between IκBα and P65. Experimental validation confirmed that FABP5 drives PD-L1 upregulation in an NF-κB–dependent manner. Drug screening identified CZS-241 as the most promising FABP5-binding candidate, and duplicate MD simulations demonstrated a stable FABP5–CZS-241 complex. Conclusion FABP5 drives immunosuppression in HCC by inducing PD-L1 via the NF-κB pathway. CZS-241 is identified as a promising FABP5-targeting compound with therapeutic potential for HCC.