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Lipid Metabolism and Disorders · Journal article
Medicine · August 7, 2026
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This Mendelian randomization study proposes a novel causal pathway in which FTO-mediated reduction of m6A modification lowers circulating 1,2-dilinoleoyl-GPC (18:2/18:2), thereby suppressing acute pancreatitis risk. The findings are based on genetic associations and metabolomic databases without experimental or clinical validation in patient cohorts.
Mendelian randomization analysis with mediating Mendelian randomization. Genetic data from individuals with acute pancreatitis and publicly available metabolomic databases; specific patient populations and recruitment sites not described. Intervention: FTO eQTL (expression quantitative trait locus) as genetic proxy for FTO-mediated m6A modification. Compared with: Genetic variants associated with acute pancreatitis risk and 1,2-dilinoleoyl-GPC (18:2/18:2) metabolite levels.
FTO eQTL was significantly negatively correlated with AP risk (OR = 0.78, 95% CI: 0.66-0.93, P <.01) FTO eQTL reduced the level of 1,2-dilinoleoyl-GPC (18:2/18:2) (OR = 0.89, 95% CI: 0.80-0.99, P <.05) High level of 1,2-dilinoleoyl-GPC (18:2/18:2) increased AP risk (OR = 1.22, 95% CI: 1.08-1.39, P <.01)
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This mechanistic hypothesis requires experimental validation and prospective clinical studies before consideration for therapeutic development. The identified metabolite could potentially serve as a biomarker or therapeutic target if the causal pathway is confirmed.
Mendelian randomization study identifying a novel causal pathway in acute pancreatitis without experimental validation or clinical outcome data in human populations.
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This mechanistic hypothesis requires experimental validation and prospective clinical studies before consideration for therapeutic development. The identified metabolite could potentially serve as a biomarker or therapeutic target if the causal pathway is confirmed.
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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.
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