Mechanisms of Sepsis From a Metabolic Immunology Perspective: A Bidirectional Mendelian Randomization and Single-Cell Sequencing Study of CD39+ Cells

Background: Interactions between immune phenotypes and metabolites in sepsis pathogenesis remain poorly defined. We integrated Mendelian randomization (MR) and single-cell transcriptomics to investigate metabolic mediation in immune-sepsis associations. Methods: Bidirectional two-sample MR analyzed sepsis genome-wide association studies (11,643 cases), 1,400 metabolites, and 731 immune phenotypes. Single-cell analysis of GSE167363 (sepsis vs. controls) included clustering, differential expression and pathway enrichment. Results: CD39 expression was upregulated in sepsis immune cells. MR-identified CD3 + CD39 + CD8 + T cells as risk factors for sepsis incidence (odds ratio = 1.053, P = 0.008) and 28-day mortality (odds ratio = 1.108, P = 0.037). These cells correlated with 73 metabolites, notably androsterone sulfate, which mediated 4.97% of sepsis risk ( P = 0.026). Conclusion: CD39 + CD8 + T cells drive sepsis progression through metabolic intermediates like androsterone sulfate, highlighting immunometabolic crosstalk as a therapeutic target.