The alternative NF-κB RelB subunit is a novel critical sensor of lipid metabolism to promote tumor development.

Cancer cells reprogram their metabolism to fulfill their high energetic demand. Lipid metabolism is most often reprogrammed for cancer cell survival and tumor development. The role of alternative oncogenic NF-κB/RelB subunit in the reprogramming of lipid metabolism in cancer is unknown. Here we report that RelB plays a central role at the crossroads of lipid storage and liberation of fatty acids from the lipid droplets to feed the fatty acid oxidation (FAO) and mitochondrial energetic metabolism. High RelB expression defines a subset of hepatocellular carcinoma (HCC) patients and cell lines with a peculiar gene expression profile enriched in lipid catabolic-related genes, including lipases. Functional studies revealed that high RelB activation controls the expression of major lipolytic lipases, including adipose triglyceride lipase (ATGL) and monoglyceride lipase (MAGL), and impacts on HCC cell survival, migration, and tumor development in vivo. Altogether, we uncovered that RelB is a central regulator of the lipid metabolism plasticity and an energy homeostasis sensor in cancer cells.