ESM1 drives cancer angiogenesis and bevacizumab resistance via trioleate synthesis.

BACKGROUND: Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor progression, yet their synergistic role in HCC lipid metabolism and angiogenesis remains unexplored. METHODS: We integrated multi-omics approaches, including RNA sequencing, metabolomics, and immunoprecipitation-mass spectrometry, in HCC cell lines and patient-derived xenograft models. Key experiments involved Co-IP, Western blotting, tube formation assays, and clinical tissue microarray analysis to validate the ESM1-ANGPTL4-FASN-trioleate axis. RESULTS: ESM1 and ANGPTL4 formed a positive feedback loop, stabilizing fatty acid synthase (FASN) to promote trioleate synthesis. Trioleate activated the NF-κB/IL-17 pathway in HCC cells and upregulated CD99 in endothelial cells, driving angiogenesis. In vivo, ESM1/ANGPTL4 knockdown suppressed tumor growth, which was rescued by trioleate supplementation. Clinical data revealed elevated ESM1/ANGPTL4 expression in bevacizumab-resistant HCC, correlating with poor prognosis. CONCLUSIONS: The ESM1-ANGPTL4-FASN-trioleate axis orchestrates metabolic reprogramming and endothelial activation, representing a promising therapeutic target. Future studies should explore combination therapies targeting this axis and overcoming bevacizumab resistance in HCC.