Abstract PR004: Lipid auxotrophy underlies ferroptosis sensitivity in clear cell renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) is a highly lethal cancer defined by abundant cytoplasmic lipid droplets and near-universal loss of the von-Hippel-Lindau gene (VHL), leading to constitutive activation of aerobic glycolysis by hypoxia-inducible factors (HIF). CcRCC is associated with accumulation of lipids including oxidation-prone polyunsaturated fatty acids (PUFAs) in lipid droplets. The origin and functional role of these lipid droplets have been insufficiently explored. We asked how ccRCC can maintain lipid stores and whether these stores are required for cell survival. We show that ccRCC cells require serum-derived lipids to preserve intracellular lipid droplets and prevent cell death. The cell death resulting from the withdrawal of serum is not associated with a bioenergetic deficit, as ccRCC maintain glucose and glutamine uptake to support bioenergetics. Even when serum-deprived, ccRCC cells do not utilize lipid droplet-derived lipids for β-oxidation-derived ATP production. Instead, preliminary data suggest that intracellular lipid stores are mobilized to support membrane biosynthesis. In the absence of exogenous lipids, de novo fatty acid synthesis is insufficient to maintain proliferation, leading to the incorporation of saturated fatty acids (SFA) and PUFA from lipid droplets into membrane phospholipids and resulting in ferroptotic cell death. Consistent with these findings, ferroptosis inhibitors and exogenous monounsaturated fatty acids (MUFA) robustly rescued proliferation in low serum. Exogenous cholesterol—despite supporting proliferation in lipid-depleted serum—did not protect against ferroptosis. Preventing the movement of fatty acids from lipid droplets to phospholipid membranes through pharmacologic inhibition of triglyceride lipolysis reduced ferroptosis sensitivity. Thus, lipid-droplet mobilization may be a key step in driving PUFA-dependent lipid peroxidation under lipid scarcity. Together, these findings demonstrate that ccRCC are auxotrophic for exogenous lipids. However, ccRCC cells do not utilize exogenous lipids for bioenergetic support. Instead, exogenous lipids stored in lipid droplets are utilized to support ccRCC cell proliferation while preventing ferroptotic cell death. Under serum-replete conditions, lipid droplets act as protective reservoirs that sequester PUFAs away from membranes; when mobilized, incorporation of stored oxidizable lipids make the cells susceptible to ferroptotic cell death. These results identify lipid auxotrophy as a potential achilles heel in ccRCC. Efforts are under way to investigate this reliance on exogenous lipids to maintain resilience to oxidative stress therapeutically. Citation Format: Ji-Young Kim, Agata A. Bielska, Michelle Saoi, Ritchie Ly, Shelby D. Brown, Tobias C. Walther, Craig B. Thompson. Lipid auxotrophy underlies ferroptosis sensitivity in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR004.