CDCA4 promotes lipid metabolism in triple-negative breast cancer through activation of the SESN2/mTOR/SREBP1 pathway

RNA-sequencing analysis indicated that CDCA4-regulated genes were significantly enriched in lipid metabolism-related pathways and metabolism-associated signaling pathways, including PI3K/AKT and mTOR. Consistently, CDCA4 depletion reduced intracellular free fatty acids, total cholesterol, triglycerides, lipid accumulation, and the expression of lipogenic enzymes, including FASN and ACC1. Mechanistically, CDCA4 promoted mTOR activation and increased the level of the active nuclear form of SREBP1, thereby enhancing SREBP1 occupancy at the FASN and ACC1 promoter regions.

Pharmacological inhibition of mTOR largely reversed CDCA4-induced malignant phenotypes and lipid metabolic alterations. Furthermore, we identified SESN2 as a critical mediator linking CDCA4 to mTOR activation, as SESN2 knockdown attenuated mTOR signaling and reversed the protumorigenic effects induced by CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid metabolic reprogramming through the SESN2/mTOR/SREBP1 axis, highlighting CDCA4 as a potential prognostic biomarker and therapeutic target in TNBC.