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This study demonstrates that regular exercise robustly enhances fear memory extinction in mice, whereas irregular exercise has only mild effects. This divergence arises from regular rather than irregular exercise strongly inhibiting axonal mRNA transport and local translation of choline acetyltransferase (ChAT) in septal cholinergic neurons projecting to the hippocampus, thereby reducing hippocampal acetylcholine (ACh) levels and inhibiting \u03b17 nicotinic acetylcholine receptor (\u03b17\u2010nAChR) activation on astrocytes. Critically, this hippocampal ACh\u2010\u03b17\u2010nAChR signaling modulates hepatic ACh via the amygdala\u2013dorsal motor nucleus of the vagus (DMV)\u2013hepatic vagus circuit. Irregular exercise inhibits this pathway inadequately, so that increasing hepatic ACh flux and recruiting a novel neutrophil subset characterized by high expression of F\u2010box and leucine\u2010rich repeat protein 6 (FBXL6\n                    <jats:sup>high<\/jats:sup>\n                    ). Subsequent abnormal iron transport from these neutrophils to hepatocytes promotes the metabolism of arachidonic acid into the proinflammatory mediators prostaglandin H2 (PGH2) and leukotriene B4 (LTB4), exacerbating nonalcoholic fatty liver disease. The findings elucidate the essential mechanisms underlying the neurometabolic benefits of regular exercise and the pathological risks of irregular exercise, offering transformative insights for preventive strategies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202500177","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:26:35Z","timestamp":1758871595000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Regular versus Irregular Exercise Differentially Modulates Hippocampal\u2010Hepatic Acetylcholine Flux to Coordinate Fear Memory Extinction and Liver Inflammation"],"prefix":"10.1002","volume":"12","author":[{"given":"Pengjiao","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Science Army Medical University  Chongqing 400038 China"},{"name":"Research Center for Nutrition and Food Safety 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