Our findings elucidate the mechanisms underlying the role of SIRT6 in ccRCC by identifying an endogenous metabolite, LPE18:1, as a novel upstream activator of SIRT6 and by elucidating ACAT2 as a key downstream effector responsible for SIRT6-mediated lipid accumulation and tumor progression. The gene discussed is SIRT6; the disease is nonpapillary renal cell carcinoma.