Integrating global burden of disease and genetic analyses to identify potential lipid-immune targets in gynecological malignancies

Abstract Background The causal relationships linking lipid metabolism, immune regulation, and gynecological malignancies remain incompletely understood, which has constrained the development of targeted therapeutic strategies for these cancers. Methods We quantified the global burden of uterine and ovarian cancers attributable to high body mass index (BMI) using Global Burden of Disease (GBD) data and projected future trends through 2031. To investigate causal mechanisms, we performed two-sample Mendelian randomization (MR) analyses ( n = 860,215) to estimate the effects of lipid species and immune cell phenotypes on gynecological malignancies risk, followed by two-step MR to quantify the mediating role of immune traits in lipid-cancer associations. Finally, we cross-referenced the identified markers against pharmacological databases (Open Targets, DrugBank, and ClinicalTrials.gov) to assess their potential translational relevance. Results BMI-attributable mortality for uterine and ovarian cancers is projected to rise persistently by 2031. We identified 30 lipid species with putative causal effects on gynecological malignancies, including protective phosphatidylcholines (PC) and triacylglycerols (TAG), as well as risk-associated species. Mediation analyses suggested that 37 immune phenotypes may mediate lipid-cancer relationships-for example, CD25⁺ B cells were associated with reduced risk, whereas programmed death-ligand 1 (PD-L1) expression on CD14 − CD16 − was linked to increased risk. Database screening yielded six lipid-modulating agents (e.g., Niacin) and 11 immune targets (e.g., PD-L1) as candidate therapeutic opportunities, with potential synergies between lipid regulators and immune checkpoint inhibitors warranting experimental exploration. Conclusions Our findings suggest that immune traits may mediate lipid-driven gynecological malignancies risk, providing a rationale for lipid-immune interventions.