{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:34:48Z","timestamp":1792010088901,"version":"4.4.0"},"reference-count":25,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovation and Entrepreneurship Training Program for College Students of China Medical University","award":["202510159037"],"award-info":[{"award-number":["202510159037"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Objectives: Exposure to high-fat diets in early life plays an important role in metabolic dysfunction-associated steatotic liver disease (MASLD); however, the mechanism remains unclear. In this study, we explore the role of autophagy and ferroptosis in pre-puberty obesity-related MASLD caused by high-fat diets in early life. Methods: Twenty-four male C57BL\/6J mice were fed over a 6-week period, and were divided into three groups: control, lactation HFD, and lactation + post-weaning HFD group. AML12 cells were treated with 0.5 mM free fatty acids (palmitic acid:oleic acid = 1:2) for 24 h to establish an in vitro model. Metabolism, autophagy, and ferroptosis-related indicators were detected. Results: Compared to the control group, the body weight, droplet deposition of the liver, Fe2+, and MDA level increased significantly in the lactation + post-weaning HFD group. Impaired autophagy, ferroptosis, and AMPK\/mTOR\/ULK1 pathway protein expression were also found in the lactation + post-weaning HFD group. Additionally, BL-918 (activate autophagy) exposure in AML12 cells may recover FFA-induced ferroptosis and disorder of lipid metabolism. Conclusions: Early-life high-fat-diet exposure induced pre-puberty obesity-related MASLD, possibly via autophagy, which may be regulated by the AMPK\/mTOR\/ULK1 pathway and mediated by ferroptosis in male mice.<\/jats:p>","DOI":"10.3390\/nu18091469","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"1469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Early-Life High-Fat-Diet Exposure Induced Pre-Puberty Obesity-Related MASLD via Autophagy-Mediated Ferroptosis in Male C57BL\/6J Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Zihan","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, China Medical University, Ministry of Education, Shenyang 110021, China"},{"name":"Department of Maternal and Child Health, School of Public Health, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Public Health, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Maternal and Child Health, School of Public Health, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Second Clinical College, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Public Health, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinran","family":"Xu","sequence":"additional","affiliation":[{"name":"Second Clinical College, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouqi","family":"Nie","sequence":"additional","affiliation":[{"name":"School of Medical Humanities, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhan","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Nursing, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianni","family":"Lv","sequence":"additional","affiliation":[{"name":"Second Clinical College, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Wu","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Center for Disease Control and Prevention, Shenyang 110172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Zhai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, China Medical University, Ministry of Education, Shenyang 110021, China"},{"name":"Department of Maternal and Child Health, School of Public Health, China Medical University, Shenyang 110021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1038\/s42255-024-01043-6","article-title":"An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"6","author":"Vacca","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/s10020-024-01003-6","article-title":"Lycorine ameliorates liver steatosis, oxidative stress, ferroptosis and intestinal homeostasis imbalance in MASLD mice","volume":"30","author":"Wang","year":"2024","journal-title":"Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.jhep.2023.01.024","article-title":"An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease","volume":"78","author":"Lee","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1002\/hep.31897","article-title":"A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD","volume":"74","author":"Im","year":"2021","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.molmed.2024.05.013","article-title":"Sexual dimorphism of metabolic dysfunction-associated steatotic liver disease","volume":"30","author":"Cherubini","year":"2024","journal-title":"Trends Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6506","DOI":"10.1038\/s41467-024-50660-y","article-title":"A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma","volume":"15","author":"Jeong","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Meyer, J., Teixeira, A.M., Richter, S., Larner, D.P., Syed, A., Kl\u00f6ting, N., Matz-Soja, M., Gaul, S., Barnikol-Oettler, A., and Kiess, W. (2025). Sex differences in diet-induced MASLD\u2014Are female mice naturally protected?. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1567573"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cavaliere, G., Catapano, A., Trinchese, G., Cimmino, F., Menale, C., Petrella, L., and Mollica, M.P. (2023). Crosstalk between Adipose Tissue and Hepatic Mitochondria in the Development of the Inflammation and Liver Injury During Ageing in High-Fat Diet Fed Rats. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032967"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Luo, J., Alkhalidy, H., Jia, Z., and Liu, D. (2024). Sulforaphane Ameliorates High-Fat-Diet-Induced Metabolic Abnormalities in Young and Middle-Aged Obese Male Mice. Foods, 13.","DOI":"10.3390\/foods13071055"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/s41418-022-00941-0","article-title":"The multifaceted role of ferroptosis in liver disease","volume":"29","author":"Chen","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhao, S., Guo, Y., and Yin, X. (2024). Autophagy, Ferroptosis, Apoptosis and Pyroptosis in Metabolic Dysfunction-Associated Steatotic Liver Disease. Front. Biosci., 29.","DOI":"10.31083\/j.fbl2901030"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1053\/j.gastro.2011.04.038","article-title":"Functions of autophagy in hepatic and pancreatic physiology and disease","volume":"140","author":"Czaja","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ceb.2009.11.014","article-title":"Mammalian autophagy: Core molecular machinery and signaling regulation","volume":"22","author":"Yang","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41574-018-0009-1","article-title":"Targeting autophagy in obesity: From pathophysiology to management","volume":"14","author":"Zhang","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113949","DOI":"10.1016\/j.expneurol.2021.113949","article-title":"High fat diet-induced obesity leads to depressive and anxiety-like behaviors in mice via AMPK\/mTOR-mediated autophagy","volume":"348","author":"Li","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1080\/15548627.2020.1712108","article-title":"SQSTM1\/p62 activates NFE2L2\/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity","volume":"16","author":"Lee","year":"2020","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/nature07976","article-title":"Autophagy regulates lipid metabolism","volume":"458","author":"Singh","year":"2009","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e71315","DOI":"10.1096\/fj.202501416RRRR","article-title":"Betaine Attenuates High-Fat-Diet-Induced Metabolism-Associated Steatotic Liver Disease via the Inhibition of Ferroptosis Through the Nrf2\/GPX4 Axis","volume":"39","author":"Zhai","year":"2025","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.freeradbiomed.2024.08.038","article-title":"Caffeic acid ameliorates metabolic dysfunction-associated steatotic liver disease via alleviating oxidative damage and lipid accumulation in hepatocytes through activating Nrf2 via targeting Keap1","volume":"224","author":"Zhang","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2412827","DOI":"10.1002\/advs.202412827","article-title":"Gut Microbiota Colonization in Early Life Influences Susceptibility to Adulthood Hepatic Lipid Accumulation in High-Fat-Diet-Fed Mice","volume":"12","author":"Zhu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e14520","DOI":"10.1111\/1751-7915.14520","article-title":"Role of breastfeeding in disease prevention","volume":"17","author":"Masi","year":"2024","journal-title":"Microb. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109017","DOI":"10.1016\/j.jnutbio.2022.109017","article-title":"Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes","volume":"106","author":"Masuda","year":"2022","journal-title":"J. Nutr. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102570","DOI":"10.1016\/j.redox.2022.102570","article-title":"Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease","volume":"59","author":"Liu","year":"2023","journal-title":"Redox Biol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/9\/1469\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:11:56Z","timestamp":1777975916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/9\/1469"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":25,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["nu18091469"],"URL":"https:\/\/doi.org\/10.3390\/nu18091469","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,5]]}}}