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April 17, 2026International Journal of Women s Health0 citationsOpen Access

Indirect Roles of Immunophenotypes in the Association Between Glycerophospholipid Metabolism and Endometrial Cancer Risk: A Mendelian Randomization Study

YSYichen ShenTianjin University of Traditional Chinese Medicine YYYijing YanChinese Academy of Medical Sciences & Peking Union Medical College PLPeizhe LinChinese Academy of Medical Sciences & Peking Union Medical College

Key Points

This research investigates the causal associations between glycerophospholipid metabolism and endometrial cancer risk, focusing on immunophenotypes' indirect roles.
Two-sample Mendelian Randomization methodology employed
Data sourced from genome-wide association studies
Multiple MR analytic approaches used including Inverse Variance Weighted and MR-Egger regression
Sensitivity analyses conducted to verify reliability of results
Genetically predicted levels of three metabolites linked to endometrial cancer risk
1-(1-enyl-palmitoyl)-GPC reduced EC risk, mediated by immunophenotypes
Eicosenedioate increased EC risk, with a significant mediating effect from CD38 on PB/PC cells
Overall indirect effects from immunophenotypes account for varying percentages of risk

Abstract

Background: The incidence of endometrial cancer (EC) has continued to rise in recent years. Increasing evidence suggests that lipid metabolic alterations in serum metabolites are associated with cancer progression. Methods: This research applied a two-step Mendelian Randomization (MR), two-sample MR methodology to explore the potential causal associations between glycerophospholipid metabolism and EC risk, as well as possible indirect roles of immunophenotypes, drawing data from the Genome-Wide Association Study Catalog and EC Association Consortium databases. The Inverse Variance Weighted, MR-Egger regression, Weighted Median Estimator, Simple Mode, and Weighted Mode approaches formed a comprehensive array of MR methodologies predominantly employed to assess causality. Several sensitivity analyses were implemented to verify the reliability of MR results. Results: Genetically predicted levels of three metabolites were associated with EC risk, with evidence suggesting partially indirect pathways involving four immunophenotypes. 1-(1-enyl-palmitoyl)-GPC (p-16:0) was found to diminish EC risk, potentially through indirect pathways involving, specifically CD33dim HLA-DR+ CD11b- AC, and CD25 on memory B cells, explaining 3.99% and 5.68% to the total effect, respectively. Additionally, 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) decreased EC risk, with partial mediation by B cell % CD3- lymphocyte, accounting for a 3.25% share of the indirect effect. Conversely, Eicosenedioate (C20:1-DC) increased EC risk, with its effect being mediated by CD38 on PB/PC cells, exerting a indirect effect of up to 10.09%. Conclusion: This investigation provides genetic evidence supporting potential causal associations between glycerophospholipid metabolism and EC, highlighting possible indirect pathways of immunophenotypes. The derived insights offer novel pathways for the diagnosis and therapeutic intervention of EC. Keywords: endometrial cancer, glycerophospholipid metabolism, immunophenotypes, mendelian randomization, indirect effects

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