2. Academic Validation
  3. Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways

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

  • Biomed Pharmacother. 2023 Jan:157:114048. doi: 10.1016/j.biopha.2022.114048.
Yu Mi 1,  Chaoqun Wei 1,  Liyao Sun 2,  Huirui Liu 1,  Jiayue Zhang 1,  Jialin Luo 2,  Xiaohan Yu 2,  Jie He 2,  Hongyan Ge 3,  Ping Liu 4
Affiliations

Affiliations

  • 1 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.
  • 2 Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China.
  • 3 Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China. Electronic address: gehongyan@hrbmu.edu.cn.
  • 4 Eye Hospital, First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Harbin 150001, China. Electronic address: liuping@hrbmu.edu.cn.
PMID: 36463827 DOI: 10.1016/j.biopha.2022.114048
Abstract

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.

Keywords

Cataract; Ferroptosis; Melatonin; SIRT6; Ultraviolet B.

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