Jiao, G.; Baracaldo Lancheros, L.; Dhiman, A.; Ferreira, C. R.; Dykhuizen, E.

Clear cell renal cell carcinoma (ccRCC) is initiated by biallelic loss of the tumor suppressor VHL followed by additional genomic alterations, including loss of tumor suppressors PBRM1, BAP1 or SETD2. Although ccRCC is known to be intrinsically sensitive to ferroptosis, the contribution of PBRM1 to this vulnerability, and how it interfaces with VHL loss, has remained unexplored. Using isogenic ccRCC and non-transformed cell models, we show that reexpression of PBRM1 and/or VHL attenuates GPX4 inhibitor induced ferroptosis, and that the two tumor suppressors act cooperatively: dual reconstitution confers the greatest protection, suppresses lipid peroxidation, and preserves redox homeostasis. Time resolved RNA-seq reveals that PBRM1 and VHL establish additive, largely non-overlapping "ground-state" transcriptional programs. Integrated pharmacogenomic, CRISPR dependency, and lipidomic analyses converge on two protective axes: restricted labile iron and MUFA biased membrane remodeling. These findings identify PBRM1 as a previously unrecognized modulator of ferroptosis and define a cooperative chromatin/metabolic axis that buffers ferroptotic cell death in ccRCC.