SREBP-1 upregulates SOAT1 to promote tumor growth by preventing lipotoxicity.

Rapidly growing tumors require abundant supplies of cholesterol, but excess cholesterol can be cytotoxic. How cancer cells balance this demand while avoiding lipotoxicity remains unclear. Our study found that SOAT1, the enzyme that converts cholesterol into cholesteryl esters for storage in lipid droplets, is concurrently upregulated with SREBP-1, a master transcription factor that governs cholesterol uptake and biosynthesis across multiple cancer types. Mechanistically, SREBP-1 binds the SOAT1 promoter and transcriptionally activates its expression, coupling cholesterol acquisition with intracellular storage. Genetic silencing of SOAT1, while preserving SREBP-1 activity, resulted in the accumulation of free cholesterol and induced mitochondrial oxidative stress, impairing the growth of patient-derived organoids and xenografts from lung cancer and glioblastoma, the most lethal brain tumor, and significantly prolonging survival in preclinical mouse models. These findings reveal a dual role of SREBP-1 in controlling both cholesterol acquisition and storage to maintain cholesterol homeostasis, prevent lipotoxicity, and sustain tumor growth.