Background: N6-methyladenosine (m6A) genes and lipid metabolism-associated genes (LMAGs) play vital roles in the tumorigenesis of pancreatic adenocarcinoma (PAAD) and have prognostic value. Thus, the identification of LMAGs associated with m6A in PAAD patients is critical. Methods: Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases (n=349), m6A-related LMAGs were obtained by coexpression analysis. A prognostic model was constructed by using the multivariate Cox regression method and validated in a dataset from the Gene Expression Omnibus (GEO) database (n = 69). Functional enrichment annotation, Kaplan-Meier analysis and principal component analysis (PCA) were used to analyse the prognostic model, and the immune microenvironment and chemotherapy response were evaluated. We performed untargeted metabolomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in tissue and serum from 10 patients with PAAD and 10 patients with benign pancreatic diseases. Finding: m6A-related LMAGs were primarily associated with the arachidonic acid and glycerophospholipid metabolism pathways. The prognostic model was constructed based on PTGES, TSPOAP1, INPP4B and HSD17B14. Low risk scores were associated with a better prognosis, a higher immune status, and greater sensitivity to 5-fluorouracil. The untargeted metabolomics results also revealed significant remodelling of lipid metabolism, especially eicosanoid and glycerophospholipid metabolism. Interpretation: This study revealed the important role of m6A modification in lipid metabolism. The risk model based on m6A-related LMAGs may be promising for the clinical prediction of prognosis and therapy in PAAD patients. \ Funding: Sichuan Science and Technology Program(2021YFS0234) Declaration of Interest: The authors declare that they have no conflicts of interest. Ethical Approval: This study was approved by the Biomedical Research Ethics Committee, West China Hospital of Sichuan University.
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