Roles of plasma proteins in mediating the causal effect of the lipid species on gastric cancer: Insights from proteomic and two-step Mendelian randomization

The change of plasma lipid species has close contacts with gastric cancer (GC). However, the specific mechanism still needs to be explored further. We aim to utilize plasma proteins to decipher the association between lipid species and GC, and seek possible drug targets for GC. We performed a two-step Mendelian randomization (MR) analysis to investigate causal relationships among 179 lipid species, 4907 plasma proteins, and GC. Using summary-data-based MR and colocalization, we first examined protein–GC associations in discovery (N = 35,559) and validation (N = 54,219) cohorts. Subsequent MR analyses assessed lipid–GC and lipid–protein relationships, followed by mediation analysis using error propagation methods. Finally, macromolecular docking of prioritized proteins identified potential therapeutic ligands. Our MR analysis revealed causal relationships between 12 lipid species and GC, as well as 3 plasma proteins and GC. Importantly, mediation analysis demonstrated that CCDC80 protein mediates 2.90% (95% CI: 0.30–5.5%) of the protective effect of diacylglycerol (16:1_18:1) against GC. Based on these findings, we identified valproic acid as a promising therapeutic candidate targeting CCDC80 for GC treatment. Our study demonstrates that reduced CCDC80 expression mediates the tumor-promoting effects of diacylglycerol (16:1_18:1) in GC pathogenesis. Molecular docking confirms valproic acid binds stably to CCDC80, suggesting its therapeutic potential. These findings advance GC etiology understanding and provide a new drug development direction.