Lipid metabolic reprogramming in clear cell renal cell carcinoma: focus on high-density lipoprotein-related pathways

Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent solid tumors characterized by lipid metabolic reprogramming, with extensive lipid droplet accumulation in tumor cells as a hallmark feature. Traditionally, this phenotypic trait is attributed to enhanced fatty acid synthesis, increased triglyceride (TG) storage, and impaired β-oxidation. However, emerging transcriptomic and lipidomic evidence suggests that cholesterol metabolism is also profoundly reprogrammed in ccRCC, particularly via increased reliance on high-density lipoprotein (HDL)-derived cholesterol. The classical fatty acid-TG pathway and the HDL-cholesterol axis are metabolically linked through shared substrates, collectively shaping lipid homeostasis in ccRCC. In this review, we summarize recent advances in ccRCC lipid metabolic reprogramming, with a focus on HDL-related cholesterol metabolism. We discuss the mechanisms involving von Hippel-Lindau (VHL) loss and hypoxia-inducible factor (HIF) activation, including SCARB1-mediated cholesterol uptake, LXRα-ABCA1/ABCG1-dependent cholesterol efflux, and SOAT1-driven re-esterification of free cholesterol into cholesteryl esters (CE). Furthermore, we outline potential therapeutic targets within these pathways and highlight critical knowledge gaps that merit further investigation. This review provides a conceptual framework for understanding HDL-centered cholesterol metabolism in ccRCC and highlights potential metabolic vulnerabilities for therapeutic targeting.