Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways

Yu Mi; Chaoqun Wei; Liyao Sun; Huirui Liu; Jiayue Zhang; Jialin Luo; Xiaohan Yu; Jie He; Hongyan Ge; Ping Liu

Biomedicine & Pharmacotherapy (Jan 2023)

Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways

Yu Mi,
Chaoqun Wei,
Liyao Sun,
Huirui Liu,
Jiayue Zhang,
Jialin Luo,
Xiaohan Yu,
Jie He,
Hongyan Ge,
Ping Liu

Affiliations

Yu Mi: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China; Key Laboratory of Ischemia-reperfusion, Harbin Medical University, Ministry of Education, Harbin 150001, China; Experimental Animal Centre, the Second Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Chaoqun Wei: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China; Key Laboratory of Ischemia-reperfusion, Harbin Medical University, Ministry of Education, Harbin 150001, China; Experimental Animal Centre, the Second Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Liyao Sun: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China
Huirui Liu: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China; Key Laboratory of Ischemia-reperfusion, Harbin Medical University, Ministry of Education, Harbin 150001, China; Experimental Animal Centre, the Second Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Jiayue Zhang: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China; Key Laboratory of Ischemia-reperfusion, Harbin Medical University, Ministry of Education, Harbin 150001, China; Experimental Animal Centre, the Second Affiliated Hospital, Harbin Medical University, Harbin 150001, China
Jialin Luo: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China
Xiaohan Yu: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China
Jie He: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China
Hongyan Ge: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China; Corresponding authors.
Ping Liu: Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China; Corresponding authors.

Journal volume & issue: Vol. 157
p. 114048

Abstract

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Summary: Background: Cataracts are the main cause of reversible blindness worldwide. The ageing of the lens caused by ultraviolet B (UVB) radiation is mostly related to oxidative stress (OS). Little is known about whether OS induced by UVB enhances the sensitivity of lens epithelial cells to ferroptotic stress, which may be a new mechanism leading to age-related cataracts (ARCs). Methods: Ferroptosis was detected by transmission electron microscopy (TEM), iron assay, lipid peroxidation (MDA) assay, real-time PCR, western blotting, and immunofluorescence. Genetic engineering technology was used to investigate the regulatory relationship among Sirtuin 6 (SIRT6), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear receptor coactivator 4 (NCOA4), glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH1). Knockdown and overexpression of SIRT6 locally in vivo in rats were performed to probe the regulatory mechanism of SIRT6 in ferroptosis in ARCs. Findings: Here, we observed that UVB can drastically induce ferroptosis in lens epithelial cells in vivo and in vitro. Surprisingly, inhibition of ferroptosis was the direct reason that melatonin rescued B-3, SRA01/04 and HEK-293 T cells survival; the pan-caspase inhibitor Z-Vad-FMK did not significantly reverse the death of UVB-irradiated cells compared with that in the UVB+DMSO group. SIRT6 was an upstream regulator of phosphorylated Nrf2 (p-Nrf2) and NCOA4 in B-3, SRA01/04 and HEK-293 T cells. Melatonin inhibited ferroptosis through the SIRT6/p-Nrf2/GPX4 and SIRT6/COA4/FTH1 pathways to neutralize lipid peroxidation toxicity, which protected cells against ferroptotic stress in vitro and delayed cataract formation caused by UVB exposure in rats. Interpretation: Our findings reveal a novel causal role of melatonin in the pathogenesis of ARCs, which raises the possibility of selectively targeting the activation of SIRT6 and ferroptotic resistance as a latent antioxidative therapeutic strategy for ARCs.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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