Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD

Fangzhi Yue; Ying Shi; Shanyu Wu; Lin Xing; Dan He; Lin Wei; Anqi Qiu; Ryan Russell; Dongmei Zhang

doi:10.1016/j.isci.2023.108560

Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD

iScience. 2023 Nov 22;26(12):108560. doi: 10.1016/j.isci.2023.108560. eCollection 2023 Dec 15.

Authors

Fangzhi Yue^{1

2}, Ying Shi¹, Shanyu Wu¹, Lin Xing¹, Dan He³, Lin Wei¹, Anqi Qiu¹, Ryan Russell⁴, Dongmei Zhang^{1

5}

Affiliations

¹ Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
² Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha 410011, Hunan, China.
³ College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
⁴ Department of Health and Human Performance, College of Health Professions, University of Texas Rio Grande Valley, Brownsville, TX, USA.
⁵ Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha 410008, China.

Abstract

Metformin prevents progression of non-alcoholic fatty liver disease (NAFLD). However, the potential mechanism is not entirely understood. Ferroptosis, a recently recognized nonapoptotic form of regulated cell death, has been reported to be involved in the pathogenesis of NAFLD. Here, we investigated the effects of metformin on ferroptosis and its potential mechanism in NAFLD. We found that metformin prevented the progression of NAFLD, and alleviated hepatic iron overload (HIO), ferroptosis and upregulated ferroportin (FPN) expression in vivo and in vitro. Mechanically, metformin reduced the lysosomal degradation pathway of FPN through activation AMPK, thus upregulated the expression of FPN protein, alleviated HIO and ferroptosis, and prevented progression of NAFLD. These findings discover a mechanism of metformin, suggesting that targeting FPN may have the therapeutic potential for treating NAFLD and related disorders.

Keywords: Biochemistry; Biological sciences; Cell biology; Pharmacology; Physiology.