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

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.

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

“…On the other hand, cAMP-PKA signaling may induce ER stress, leading to autophagy-induced degradation of ferritin heavy chain 1, intracellular accumulation of Fe 2+ , and ferroptosis [ 49 ]. However, recent studies indicate that PKA may inhibit ER stress and ferroptosis as well [ 50 ]. Thus, the effects of cAMP and PKA on ferroptosis may be context-dependent.…”

The potential influence of melatonin on mitochondrial quality control: a review

“…In the cytoplasm, melatonin can directly bind to nuclear receptors (retinoid-related orphan nuclear hormone receptor family) ( Carlberg and Wiesenberg, 1995 ; Karasek et al, 2003 ; Ma et al, 2021 ). Besides nucleus, melatonin also exhibits regulatory effects by modulating endoplasmic reticulum (ER) stress ( Martínez-Campa et al, 2006 ; Wu et al, 2016 ; Xue et al, 2017 ; Fang et al, 2018 ; Shi et al, 2018 ; Lee et al, 2019 ; Fan et al, 2020 ; Mahalanobish et al, 2020 ; Zhang et al, 2020 ; Guan et al, 2023 ). Additionally, melatonin can be transported into mitochondria through PEPT1/2 ( Huo et al, 2017 ).…”

Systematic analysis of the relationship between non-alcoholic fatty liver disease and tissue iron overload: promising areas for the use of polypeptide therapy

“…Мелатонин снижает ферроптоз печени на модели НАЖБП у мышей путем ингибирования клеточного окислительного стресса через сигнальный путь MT2/ cAMP/PKA/IRE1 и, тем самым, тормозит прогрессирование НАЖБП [60]. Куркумол (из экстракта куркумы) ингибирует ферритинофагию, сдерживая старение гепатоцитов посредством YAP/NCOA4 при НАЖБП [61].…”