Lipid metabolism reprogramming in endometrial cancer: biologic underpinnings, prognostic implications, and therapeutic opportunities

Abstract Endometrial cancer is strongly associated with obesity and other metabolic disorders, but host-level associations do not necessarily imply that tumor cells depend on a specific lipid pathway. This review therefore considers two related questions: how obesity, insulin resistance, and dyslipidemia influence endometrial cancer risk and outcome, and what evidence supports tumor-intrinsic changes in lipid uptake, fatty acid synthesis and desaturation, fatty acid oxidation, and cholesterol or oxysterol signaling. Endometrial cancer-specific studies provide preclinical support for ATP-citrate lyase (ACLY), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), acyl-CoA synthetase long-chain family member 1 (ACSL1), squalene epoxidase (SQLE), and liver X receptor alpha (LXRα), which is encoded by nuclear receptor subfamily 1 group H member 3 (NR1H3). Evidence for circulating lipids and tissue markers is less mature: most studies are observational, retrospective, or based on cell lines and xenografts, and standardized assays and clinically validated cutoffs are lacking. Statins, fatostatin, SQLE inhibition, and fatty acid synthase inhibition illustrate possible therapeutic approaches, but no lipid-directed treatment has established efficacy in an endometrial cancer-specific clinical trial. The available literature supports continued mechanistic and biomarker work, provided that host metabolic measures, tumor pathway dependence, and treatment-predictive value are evaluated as separate evidence categories.