Abstract
Acute pancreatitis (AP) is an inflammatory disorder with a rising global incidence and substantial morbidity and mortality; however, its molecular pathogenesis remains unclear. Epigenetic regulation by N6-methyladenosine (m6A) RNA modification is increasingly being recognized as a key mechanism in immune and inflammatory diseases. However, the causal role of m6A-related genes and their immunological mediators in AP has not been elucidated. We performed 2-sample Mendelian randomization (MR) analysis to assess the causal relationship between m6A gene expression and AP risk using cis-eQTL data from the eQTLGen consortium and genome-wide association studies summary statistics from 855,309 individuals of European ancestry. Summary-data-based MR (SMR) and heterogeneity in dependent instruments tests were conducted to validate causality and to exclude linkage bias. Furthermore, a 2-step MR mediation analysis was performed using 612 immune cell traits from the Integrative Epidemiology Unit OpenGWAS database to identify downstream immune mediators. Among the 12 m6A genes with valid cis-eQTL instruments, only YTHDF3 demonstrated a significant protective effect against AP (OR = 0.876, 95% CI: 0.795-0.966, P = .0078). SMR analysis confirmed this association (b_SMR = -0.176, P = .0106) without evidence of heterogeneity (P_heterogeneity in dependent instruments = 0.451). Mediation analysis identified CD45RA+ resting regulatory T cells as a partial mediator of YTHDF3's effect (βa = 0.2758; β_b = -0.0297), with an indirect effect accounting for 6.18% of the total causal pathway. Our study identified YTHDF3 as a novel protective gene for AP and suggested that its effect is partially mediated by CD45RA+ resting Treg cells. These findings reveal a previously unrecognized m6A-immune axis and offer potential biomarkers and targets for immunomodulatory interventions in AP.