Early-Life High-Fat-Diet Exposure Induced Pre-Puberty Obesity-Related MASLD via Autophagy-Mediated Ferroptosis in Male C57BL/6J Mice
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Updated: May 14, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Zihan Zhang1,2, Yan Wu3, Xiaoqing Wu2
1Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, China Medical University, Ministry of Education, Shenyang 110021, China.
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.
