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Hesperetin, a dietary citrus flavonoid, was evaluated for its hepatoprotective mechanism using high-fat diet\u2013induced MASLD mice and free fatty acid\u2013challenged hepatocytes. Hesperetin improved glucose and lipid metabolism, alleviated steatosis and inflammation, and restored hepatic function. Integrated transcriptomics and network analysis indicated activation of retinol metabolism and inhibition of MAPK signaling. Mechanistic studies showed that hesperetin suppressed aberrant MAPK activity, preserved retinoic acid receptor \u03b1 (RAR\u03b1) function, upregulated RAR\u03b1-dependent metabolic genes, and reduced lipogenic gene expression. Pharmacological blockade or siRNA knockdown of RAR\u03b1 abrogated hesperetin\u2019s lipid-lowering effects, confirming RAR\u03b1 as an essential mediator. These findings identify hesperetin as a food-derived modulator of the MAPK\u2013RAR\u03b1 axis that restores retinoid signaling and ameliorates hepatic lipid dysregulation, highlighting its potential as a targeted nutritional strategy for MASLD management.<\/jats:p>","DOI":"10.1021\/acs.jafc.5c16995","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T02:05:02Z","timestamp":1787364302000},"page":"27055-27074","source":"Crossref","is-referenced-by-count":0,"title":["Dietary Citrus\nFlavonoid Hesperetin Attenuates Metabolic\nDysfunction\u2013Associated Steatotic Liver Disease via Modulation\nof MAPK\u2013RAR\u03b1 Axis"],"prefix":"10.1021","volume":"74","author":[{"given":"Yilong","family":"Fu","sequence":"first","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]},{"name":"Zhejiang University School of Medicine , , ,","place":["Hangzhou, China, 310016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyou","family":"Lin","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]},{"name":"Zhejiang University School of Medicine , , ,","place":["Hangzhou, China, 310016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fucai","family":"Liu","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0099-5652","authenticated-orcid":true,"given":"Jiannan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2465-3079","authenticated-orcid":true,"given":"Xiaobing","family":"Dou","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]},{"name":"Zhejiang University School of Medicine , , ,","place":["Hangzhou, China, 310016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9423-9201","authenticated-orcid":true,"given":"Xiao","family":"Liang","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University , , , ,","place":["Hangzhou, Zhejiang, China, 310053"]},{"name":"Zhejiang University School of Medicine , , ,","place":["Hangzhou, China, 310016"]},{"name":"Wenzhou Medical University , , ,","place":["Wenzhou, Zhejiang, China, 325035"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"3","key":"2026090311502882900_cit1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.7570\/jomes23052","article-title":"Metabolic Dysfunction-Associated Steatotic Liver Disease\n(MASLD): A State-of-the-Art Review","volume":"32","author":"Chan","year":"2023","journal-title":"J. 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