This mechanistic cascade resolves a critical knowledge gap by linking membrane phospholipid derivatives to cholesterol deposition—a nexus of particular relevance given the characteristic lipid droplet accumulation in ccRCC.42,43 Notably, our discovery that the CAPZA1/USP48 interaction shields SIRT6 from proteasomal degradation adds nuance to previous reports of USP-mediated stabilization in other cancers, while the SIRT6-ACAT2 axis introduces a novel metabolic vulnerability specific to renal malignancies (Fig. 10). Here, ACAT2 is linked to nonpapillary renal cell carcinoma.