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Methods: Fifty male C57BL\/6J mice were randomized into five groups: control group (CN), high-fat diet group (HD), FA supplementation group (HF), MLT supplementation group (HM), and FA combined with MLT supplementation group (HFM). The experiment lasted for 10 weeks. Results: FA combined with MLT effectively inhibited HFD-induced increases in liver index, hepatic TG levels, and serum TG levels. Histological examination revealed that FA combined with MLT significantly reduced the area of hepatic steatosis and the accumulation of lipid droplets (LD). Western blot analysis showed FA combined with MLT activated AMPK, inhibiting the expression of ERS-related proteins, thereby reducing the expression of LD lipolysis-associated proteins. Conclusions: FA combined with MLT might prevent HFD-induced hepatic steatosis by attenuating ERS and subsequently promoting LD lipolysis.<\/jats:p>","DOI":"10.3390\/nu17233641","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T12:41:58Z","timestamp":1763728918000},"page":"3641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Folic Acid Combined with Melatonin Might Prevent Hepatic Steatosis by Alleviating Endoplasmic Reticulum Stress to Promote Lipid Droplet Lipolysis in High-Fat Diet-Fed Mice"],"prefix":"10.3390","volume":"17","author":[{"given":"Dan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhen","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixian","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5376-1456","authenticated-orcid":false,"given":"Xi","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0675-6963","authenticated-orcid":false,"given":"Hui","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, 308 Ningxia Road, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement","volume":"73","author":"Eslam","year":"2020","journal-title":"J. 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