Integrating plasma metabolomics, Mendelian randomization, and machine learning, this study identified phenylalanine as causally associated with pancreatic cancer among 55 plasma metabolites (IVW OR = 1.641, 95% CI 1.052–2.562, p = 0.029), derived eight related differentially expressed genes, built a random forest diagnostic model from 113 combinations of 12 algorithms (training AUC 0.994; validation AUCs 0.918, 0.983, 0.923), used SHAP to rank SLC6A14 as the top feature, and combined single-cell sequencing, simulated gene knockout, molecular docking, and molecular dynamics to suggest genistein binds SLC6A14 stably, with RT-qPCR confirming high expression of the five model genes in a BxPC-3 versus HPDE6-C7 cell pair.
Integrating plasma metabolomics, Mendelian randomization, and machine learning, this study identified phenylalanine as causally associated with pancreatic cancer among 55 plasma metabolites (IVW OR = 1.641, 95% CI 1.052–2.562, p = 0.029), derived eight related differentially expressed genes, built a random forest diagnostic model from 113 combinations of 12 algorithms (training AUC 0.994; validation AUCs 0.918, 0.983, 0.923), used SHAP to rank SLC6A14 as the top feature, and combined single-cell sequencing, simulated gene knockout, molecular docking, and molecular dynamics to suggest genistein binds SLC6A14 stably, with RT-qPCR confirming high expression of the five model genes in a BxPC-3 versus HPDE6-C7 cell pair.