Linking 91 inflammatory cytokines to testicular cancer through metabolites: An exploratory two-step Mendelian randomization study.

Testicular cancer (TC) is one of the most common malignancies among men aged 15 to 35 and exhibits an increasing global incidence. While some genetic risks are known, nongenetic factors like chronic inflammation and metabolic dysregulation might account for over half of its susceptibility. Research on TC's inflammatory regulation is limited, and traditional studies cannot clearly distinguish causal effects. The key is to clarify the causal link between 91 inflammatory cytokines and TC and explore the mediating role of 1400 metabolites. A two-step Mendelian randomization (MR) study used large-scale genome-wide association datasets. In step 1, a two-sample MR and reverse MR analyzed the cytokine-cancer relationship. Step 2 evaluated metabolites' mediating role. R software packages with multiple methods (inverse variance weighted as the main, others as supportive) were used, along with sensitivity analyses. Six cytokines had causal associations with TC. Interleukin-7 (odds ratios [OR] = 1.88, P = .022), interleukin-2 receptor subunit beta (OR = 1.63, P = .017), and interleukin-5 (OR = 1.56, P = .039) were positively associated with TC risk, while tumor necrosis factor ligand superfamily member 14 (OR = 0.65, P = .023), programmed cell death 1 ligand 1 (OR = 0.58, P = .017), and interleukin-24 (OR = 0.48, P = .023) showed protective effects. Additionally, 53 metabolites were linked to the cancer, and 6 mediated the relationship between 2 cytokines and TC. The study found 6 cytokine-cancer causal links and 6 mediating relationships. Studying metabolites and cytokines offers a new way to understand TC pathogenesis.