SREBP1-activated lipid metabolism drives ferroptosis and progression of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) exhibits aberrant lipid synthesis, yet how this metabolic reprogramming influences ferroptosis—a form of regulated cell death driven by lipid peroxidation—remains poorly understood. This study demonstrates that the key lipid transcription factor SREBP1 acts as a master regulator that promotes ccRCC progression by suppressing ferroptosis. Using SREBP1-knockdown cell models, we found that SREBP1 depletion enriches ferroptosis-related pathways and enhances ferroptosis sensitivity, as evidenced by elevated mitochondrial ROS, labile iron pool, PE-OOH levels, and characteristic mitochondrial alterations. Mechanistically, SREBP1 transcriptionally represses the pro-ferroptotic gene ACSL4 while simultaneously activating the lipid-synthesis gene FASN. Rescue experiments revealed that modulating either ACSL4 or FASN alone only partially reverses the ferroptosis phenotype induced by SREBP1 loss, whereas dual manipulation of both genes fully restores ferroptosis resistance. Metabolomic analyses showed that ACSL4 and FASN converge to regulate the cellular PUFAs/MUFAs ratio, which in turn feeds back to modulate SREBP1 nuclear translocation, thereby establishing a self-reinforcing positive-feedback loop. Clinically, low ACSL4 expression correlates with advanced tumor stage and poor patient survival. In vivo, SREBP1 promotes tumor growth by inhibiting ferroptosis via the ACSL4/FASN axis. Collectively, our findings reveal that SREBP1 drives ccRCC malignancy through a dual-pronged mechanism—repressing ACSL4 and activating FASN—to alter the PUFAs/MUFAs balance and establish a feed-forward loop that sustains ferroptosis suppression. ACSL4 represents a potential prognostic biomarker, and targeting the SREBP1-ACSL4/FASN axis offers a promising therapeutic strategy for ccRCC.