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However, few studies have been conducted in aquatic animals on the relationship between m6A methylation modification and autophagy-inflammation induced by lipid metabolism disorders. In the present study, a high-fat (HF) group and HF-MLP group (1 g mulberry leaf polysaccharides (MLPs)\/1 kg HF diet) were set up. The mid-hind intestines of Megalobrama amblycephala juveniles from the two groups were collected for MeRIP-seq and RNA-seq after an 8-week feeding trial. The m6A peaks in the HF and HF-MLP groups were mainly enriched in the 3\u2032 Untranslated Region (3\u2032UTR), Stop codon, and coding sequence (CDS) region. Compared with the HF group, the m6A peaks in the HF-MLP group were shifted toward the 5\u2032UTR region. \u2018RRACH\u2019 was the common m6A methylation motif in the HF and HF-MLP groups. Methyltransferase mettl14 and wtap expression in the intestines of the HF-MLP group were significantly higher compared with the HF group (p &lt; 0.05). A total of 21 differentially expressed genes(DEGs) with different peaks were screened by the combined MeRIP-seq and RNA-seq analysis. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis enriched BCL2 interacting protein 3 (bnip3) to autophagy\u2013animal and mitophagy\u2013animal signaling pathways, etc., and nucleotide-binding domain leucine-rich repeat protein 1 (nlrp1) was enriched to the Nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway. Combined MeRIP-seq and RNA-seq analysis indicated that the expression pattern of bnip3 was hyper-up and that of nlrp1 was hyper-down. Gene Set Enrichment Analysis (GSEA) analysis confirmed that the intestinal genes of HF-MLP group positively regulate lysosomal and autophagy\u2013animal signaling pathways. In the present study, we demonstrated that m6A methylation modification plays a role in regulating autophagy-inflammatory responses induced by HF diets by MLPs, and further explored the molecular mechanisms by which MLPs work from the epigenetic perspective.<\/jats:p>","DOI":"10.3390\/ijms26094345","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:28:11Z","timestamp":1746174491000},"page":"4345","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["m6A Methylation Mediated Autophagy and Nucleotide-Binding Oligomerization Domain-like Receptors Signaling Pathway Provides New Insight into the Mitigation of Oxidative Damage by Mulberry Leaf Polysaccharides"],"prefix":"10.3390","volume":"26","author":[{"given":"Wenqiang","family":"Jiang","sequence":"first","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China"},{"name":"Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjie","family":"Qian","sequence":"additional","affiliation":[{"name":"Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyue","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyan","family":"Gu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianping","family":"Ge","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China"},{"name":"Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8008-3560","authenticated-orcid":false,"given":"Linghong","family":"Miao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China"},{"name":"Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"ref_1","unstructured":"The Bureau of Fisheries and Fishery Administration tMoA, National Fisheries Technology Extension Center, Fisheries (2023). 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