Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor essential for cancer cell survival. The reprogramming of lipid metabolism has emerged as a hallmark of cancer, yet the relevance of HIF-1 alpha to this process remains elusive. In this study, we profile HIF-1 alpha -interacting proteins using proteomics analysis and identify fatty acid-binding protein 5 (FABP5) as a critical HIF-1 alpha -binding partner. In hepatocellular carcinoma (HCC) tissues, both FABP5 and HIF-1 alpha are upregulated, and their expression levels are associated with poor prognosis. FABP5 enhances HIF-1 alpha activity by promoting HIF-1 alpha synthesis while disrupting FIH/HIF-1 alpha interaction at the same time. Oleic-acid treatment activates the FABP5/HIF-1 alpha axis, thereby promoting lipid accumulation and cell proliferation in HCC cells. Our results indicate that fatty-acid-induced FABP5 upregulation drives HCC progression through HIF-1-driven lipid metabolism reprogramming. Seo et al. identify fatty acid-binding protein 5 (FABP5) as a booster of HIF-1 alpha activity. They find that oleic-acid treatment activates the FABP5/HIF-1 alpha axis, promoting lipid accumulation and cell proliferation in liver cancer cells. This study provides insights into how fatty acids drive the progression of cancer.