Background and Aims:Pancreatic cancer(PC)is a highly lethal malignancy with poor prognosis and limited early diagnostic tools.Although numerous serum metabolites have been associated with PC risk in observational studies,the causal nature of these associations remains uncertain.This study aimed to evaluate the genetic causal relationships between serum metabolites and PC risk,identify PC-related risk genes,and elucidate the gene-metabolite-PC causal network.Methods:Two-sample Mendelian randomization(TSMR)and summary-data-based Mendelian randomization(SMR)analyses were performed by integrating GWAS data of 325 serum metabolites,GTEx v8 pancreatic tissue eQTL data,and FinnGen R12 PC GWAS data.The study assessed causal effects of metabolites on PC risk,identified risk-associated genes,and explored the potential mediating role of metabolites between genes and PC.Results:Four serum metabolites showed significant causal relationships with PC risk.Elevated serum albumin(OR=1.456,P=0.003)and free cholesterol percentage in small high-density lipoprotein(HDL)(OR=1.189,P=0.005)were associated with increased PC risk,whereas higher phospholipid percentages in intermediate-density lipoprotein(IDL)and small HDL were protective(OR=0.792 and 0.836,respectively;both P<0.01).SMR analysis identified 196 PC-related genes,including risk genes such as DGKQ,CDC37P1,and SULT1A2,and protective genes such as PALMD and HEG1.Thirty-two significant gene-metabolite causal pairs were further confirmed,indicating potential mediation of PC genetic risk through specific metabolic pathways.Conclusion:This study systematically clarified the causal relationships between serum metabolites and pancreatic cancer risk and established a gene-metabolite regulatory network.The findings highlight the central role of lipid metabolism in PC development and provide molecular evidence for early detection and personalized prevention strategies.

Background and Aims:Pancreatic cancer(PC)is a highly lethal malignancy with poor prognosis and limited early diagnostic tools.Although numerous serum metabolites have been associated with PC risk in observational studies,the causal nature of these associations remains uncertain.This study aimed to evaluate the genetic causal relationships between serum metabolites and PC risk,identify PC-related risk genes,and elucidate the gene-metabolite-PC causal network.Methods:Two-sample Mendelian randomization(TSMR)and summary-data-based Mendelian randomization(SMR)analyses were performed by integrating GWAS data of 325 serum metabolites,GTEx v8 pancreatic tissue eQTL data,and FinnGen R12 PC GWAS data.The study assessed causal effects of metabolites on PC risk,identified risk-associated genes,and explored the potential mediating role of metabolites between genes and PC.Results:Four serum metabolites showed significant causal relationships with PC risk.Elevated serum albumin(OR=1.456,P=0.003)and free cholesterol percentage in small high-density lipoprotein(HDL)(OR=1.189,P=0.005)were associated with increased PC risk,whereas higher phospholipid percentages in intermediate-density lipoprotein(IDL)and small HDL were protective(OR=0.792 and 0.836,respectively;both P<0.01).SMR analysis identified 196 PC-related genes,including risk genes such as DGKQ,CDC37P1,and SULT1A2,and protective genes such as PALMD and HEG1.Thirty-two significant gene-metabolite causal pairs were further confirmed,indicating potential mediation of PC genetic risk through specific metabolic pathways.Conclusion:This study systematically clarified the causal relationships between serum metabolites and pancreatic cancer risk and established a gene-metabolite regulatory network.The findings highlight the central role of lipid metabolism in PC development and provide molecular evidence for early detection and personalized prevention strategies.