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FTO-mediated m6A modification suppresses acute pancreatitis by downregulating 1,2-dilinoleoyl-GPC (18:2/18:2): An

Huan Liang1, Geng Su, Shengjie Zheng

  • 1Emergency Medicine Department, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.

Medicine
|August 7, 2026
PubMed

Insights

The fat mass and obesity (FTO) gene influences acute pancreatitis (AP) risk by regulating N6-methyladenosine (m6A) modification. FTO lowers levels of the metabolite 1,2-dilinoleoyl-GPC, thereby suppressing AP development.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolomics

Background:

  • Acute pancreatitis (AP) pathophysiology is not fully understood.
  • N6-methyladenosine (m6A) modification and metabolites are implicated in AP pathogenesis.
  • Precise molecular mechanisms linking m6A, metabolites, and AP remain unclear.

Purpose of the Study:

  • To investigate causal pathways in AP pathogenesis using multi-omics data.
  • To evaluate the relationship between m6A-related genes, metabolites, and AP risk.
  • To identify novel regulatory axes involved in AP development.

Main Methods:

  • Integrated multi-omics data including AP genetic statistics, eQTL data, and plasma metabolite information.
  • Employed Mendelian randomization and mediating Mendelian randomization for causal inference.
  • Conducted sensitivity analyses including leave-one-out, heterogeneity, and horizontal pleiotropy tests.

Main Results:

  • The fat mass and obesity (FTO) eQTL showed a significant negative correlation with AP risk (OR=0.78).
  • FTO eQTL reduced 1,2-dilinoleoyl-glycerophosphocholine (1,2-dilinoleoyl-GPC) levels (OR=0.89).
  • Elevated 1,2-dilinoleoyl-GPC levels increased AP risk (OR=1.22).

Conclusions:

  • A novel regulatory axis, FTO-m6A-1,2-dilinoleoyl-GPC, was identified in AP.
  • FTO-mediated demethylation lowers 1,2-dilinoleoyl-GPC, suppressing AP.
  • FTO promotes phospholipid metabolic reprogramming via m6A, inhibiting AP development, offering therapeutic targets.
Keywords:
1,2-dilinoleoyl-GPC (18:2/18:2)FTOacute pancreatitism6A

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