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Previous studies have shown that indole\u20103\u2010propionic acid (IPA) can ameliorate MAFLD; however, the regulatory mechanism by which IPA affects lipid synthesis requires further investigation. In\u00a0vitro, FFA\u2010induced HepG2 cells were treated with IPA (15\u201335\u2009\u03bcM), and hepatic lipid accumulation was evaluated by Oil Red O staining. RNA\u2010seq and Western blotting were employed to analyze AHR\/AMPK signaling activation, and pharmacological inhibitors and agonists targeting AHR and AMPK were applied to explore the regulatory mechanism of IPA on lipid deposition. In\u00a0vivo, C57BL\/6J mice on a high\u2010fat diet received 50\u2009mg\/kg IPA for 16\u2009weeks, followed by histopathological evaluation and assessment of AHR\/AMPK pathway activation. Results showed that IPA dose\u2010dependently reduced lipid deposition in HepG2 cells. IPA inhibited lipid synthesis by activating AHR (inducing CYP1A1 expression and nuclear translocation) and promoting AMPK phosphorylation, thereby downregulating SREBP\u20101c and FAS expression. Pharmacological experiments demonstrated that IPA\u2010induced AMPK activation was dependent on AHR nuclear translocation. Moreover, phosphorylated AMPK further promoted AHR nuclear translocation, indicating the existence of a potential bidirectional crosstalk between AHR and AMPK. In animal studies, IPA mitigated HFD\u2010induced hepatic steatosis through activation of the AHR\/AMPK signaling pathways. In conclusion, indole\u20103\u2010propionic acid may alleviate MAFLD by ameliorating high\u2010fat diet\u2010induced hepatic lipid deposition through AHR\/AMPK signaling activation.<\/jats:p>","DOI":"10.1002\/fsn3.72206","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T09:47:12Z","timestamp":1786096032000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Indole\u20103\u2010Propionic Acid Alleviates Metabolic Dysfunction\u2010Associated Fatty Liver Disease via\n                    <scp>AHR<\/scp>\n                    \/\n                    <scp>AMPK<\/scp>\n                    Signaling Activation"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2746-398X","authenticated-orcid":false,"given":"Yanting","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health Guangzhou Medical 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