FTO-mediated m6A modification suppresses acute pancreatitis by downregulating 1,2-dilinoleoyl-GPC (18:2/18:2): An integrated multi-omics mechanistic study.

The pathophysiology of acute pancreatitis (AP), a common clinical emergency, is poorly understood. Previous studies have implicated N6-methyladenosine (m6A) modification in the pathogenesis of AP; however, the precise molecular mechanisms remain unclear. Whether metabolites participate in this process is also an important, unresolved question. To investigate the possible causal pathways, we integrated multi-omics data. We identified m6A related genes from literature and combined these genes with genetic summary statistics of AP, expression quantitative trait loci (eQTL) data, and information on 1400 plasma metabolites from public databases. We constructed a causal inference framework based on these data. The causal relationship between m6A-related genes, metabolites, and AP risk was systematically evaluated using Mendelian randomization and mediating Mendelian randomization methods. To validate the reliability of our results, we performed leave-one-out sensitivity, heterogeneity tests, and horizontal pleiotropy. We found that the fat mass and obesity (FTO) eQTL was significantly negatively correlated with AP risk (odds ratio [OR] = 0.78, 95% confidence interval [CI]: 0.66–0.93, P  < .01). In addition, we found that the FTO eQTL reduced the level of 1,2-dilinoleoyl-glycerophosphocholine (1,2-dilinoleoyl-GPC, 18:2/18:2; OR = 0.89, 95% CI: 0.80–0.99, P < .05) and that a high level of this metabolite increased the risk of AP (OR = 1.22, 95% CI: 1.08–1.39, P  < .01). Therefore, we constructed and verified a regulatory axis named “FTO–m6A–1,2-dilinoleoyl-GPC (18:2/18:2) “: Through its role in diminishing m6A modification levels, FTO-mediated demethylation lowers circulating 1,2-dilinoleoyl-GPC (18:2/18:2), which contributes to the suppression of AP. This is the first time that we have discovered the “FTO–m6A–1,2-dilinoleoyl-GPC (18:2/18:2)” regulatory axis in AP. We found that FTO may promotes phospholipid metabolic reprogramming by stimulating an m6A-dependent posttranscriptional mechanism, which further inhibited disease development. These findings provide new insights into the process of AP and new directions for targeted therapy.