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Int J Biol Sci 2023; 19(12):3937-3950. doi:10.7150/ijbs.85883 This issue Cite

Research Paper

Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway

Qingyun Guan¹, Zixu Wang¹, Keyu Hu¹, Jing Cao¹, Yulan Dong¹, Yaoxing Chen^1,2✉

1. College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China.
2. Department of Nutrition and Health, China Agricultural University, Haidian, Beijing 100193, China.

✉ Corresponding author: Yaoxing Chen, Professor, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing, 100193, China; E-mail: yxchenedu.cn.

Abstract

Ferroptosis, an iron-dependent cell death form, has recently been observed in the development of non-alcoholic fatty liver disease (NAFLD). Melatonin (Mel) shows potential benefits for preventing and treating liver diseases. Whether and how Mel ameliorates hepatic ferroptosis in NAFLD is not fully understood. Here we established a mouse model of NAFLD induced by long-term high-fat diet (HFD) feeding. We found that Mel treatment ameliorated global metabolic abnormalities and inhibited the progression of NAFLD in mice. Most importantly, Mel supplementation significantly improved HFD-induced iron homeostasis disorders in the liver, including iron overload and ferritin transport disorders. For another, Mel ameliorated HFD-induced hepatic lipid peroxidation. The recuperative role of exogenous Mel on hepatocyte ferroptosis was also observed in PA- or Erastin-treated HepG2 cells. Mechanistically, MT2, but not MT1, was involved in the effect of Mel. Furthermore, Mel treatment inhibited HFD or Erastin-activated ER stress and activated the PKA/IRE1 signaling pathway. Co-expression of p-PKA and p-IRE1 was enhanced by the MT2 antagonist. Inhibitions of PKA and IRE1 respectively improved hepatocyte ferroptosis, and activations of cAMP/PKA reversed Mel's effect on ferroptosis. Collectively, these findings suggest that exogenous Mel inhibits hepatic ferroptosis in NAFLD by ameliorating ER stress through the MT2/cAMP/PKA/IRE1 pathway, proving that Mel is a promising candidate drug for the treatment of hepatic ferroptosis in NAFLD.

Keywords: Melatonin, NAFLD, Liver, Ferroptosis, MT2, ER stress, IRE1

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