De Novo Lipogenesis in Clear Cell Renal Cell Carcinoma: Mechanistic Insights and Therapeutic Implications.

Clear cell renal cell carcinoma (ccRCC) is increasingly recognized as a lipid-addicted malignancy in which de novo lipogenesis (DNL) supports tumor growth, survival, and treatment resistance. ccRCC-specific genetic alterations, particularly loss of VHL and activation of hypoxia-inducible factor (HIF) signaling, promote SREBP-mediated upregulation of key lipogenic enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1). These pathways support membrane biogenesis and redox balance while also promoting metabolic flexibility, enabling adaptation to therapeutic and microenvironmental stresses. Emerging preclinical studies suggest that pharmacological inhibition of lipogenic enzymes, either alone or in combination with tyrosine kinase inhibitors, mTOR inhibitors, HIF-2α antagonists, or immune checkpoint blockade, may suppress ccRCC progression. However, most therapeutic data remain limited to preclinical models, and clinical validation is still lacking. This review synthesizes recent advances in molecular regulation and therapeutic targeting of DNL in ccRCC and discusses the challenges and future opportunities to improve mechanistic understanding and explore potential therapeutic applications.