2. Academic Validation
  3. Metformin improves nonalcoholic fatty liver disease in db/db mice by inhibiting ferroptosis

Metformin improves nonalcoholic fatty liver disease in db/db mice by inhibiting ferroptosis

  • Eur J Pharmacol. 2024 Jan 18:966:176341. doi: 10.1016/j.ejphar.2024.176341.
Teng Zhang 1,  Meng-Yan Wang 2,  Guo-Dong Wang 3,  Qiu-Yue Lv 4,  Yu-Qian Huang 5,  Peng Zhang 6,  Wen Wang 7,  Yan Zhang 8,  Ya-Ping Bai 9,  Li-Qun Guo 10
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: zt18895380684@163.com.
  • 2 School of Pharmacy, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical College, Wuhu, 241002, China. Electronic address: wangmengyan999@163.com.
  • 3 School of Pharmacy, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical College, Wuhu, 241002, China. Electronic address: wangguodong@wnmc.edu.cn.
  • 4 School of Pharmacy, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical College, Wuhu, 241002, China. Electronic address: lqiuyue@126.com.
  • 5 School of Pharmacy, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical College, Wuhu, 241002, China. Electronic address: 449241362@qq.com.
  • 6 Department of Laboratory Medicine, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: zp2169@163.com.
  • 7 Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: 403215973@qq.com.
  • 8 Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. Electronic address: yanyan0921@sina.com.
  • 9 Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, College of Life Sciences, Anhui Normal University, Wuhu, 241000, China. Electronic address: ya19855363005@163.com.
  • 10 School of Pharmacy, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical College, Wuhu, 241002, China. Electronic address: wy_glq@wnmc.edu.cn.
PMID: 38244761 DOI: 10.1016/j.ejphar.2024.176341
Abstract

Nonalcoholic fatty liver disease (NAFLD) is the primary complication of type 2 diabetes (T2DM)-related liver disease, lacking effective treatment options. Metformin (Met), a widely prescribed anti-hyperglycemic medication, has been found to protect against NAFLD. Ferroptosis, a newly discovered form of cell death, is associated with the development of NAFLD. Despite this association, the extent of Met's protective effects on NAFLD through the modulation of Ferroptosis has yet to be thoroughly investigated. In the present study, the administration of erastin or Ras-selective lethal 3 (RSL3), both known Ferroptosis inducers, resulted in elevated cell mortality and reduced cell viability in AML12 hepatocytes. Notably, Met treatment demonstrated the capacity to mitigate these effects. Furthermore, we observed increased Ferroptosis levels in both AML12 hepatocytes treated with palmitate and oleate (PA/OA) and in the liver tissue of db/db mice. Met treatment demonstrated significant reductions in iron accumulation and lipid-related Reactive Oxygen Species production, simultaneously elevating the glutathione/glutathione disulfide ratio in both PA/OA-treated AML12 hepatocytes and the liver tissue of db/db mice. Interestingly, the anti-ferroptosis effects of Met were significantly reversed with the administration of RSL3, both in vitro and in vivo. Mechanistically, Met treatment regulated the Glutathione Peroxidase 4/solute carrier family 7 member 11/acyl-CoA synthetase long-chain family member 4 axis to alleviate Ferroptosis in NAFLD hepatocytes. Overall, our findings highlight the crucial role of Ferroptosis in the development of T2DM-related NAFLD and underscore the potential of Met in modulating key factors associated with Ferroptosis in the context of NAFLD.

Keywords

Ferroptosis; Metformin; Nonalcoholic fatty liver disease.

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