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

Yu, Miao; Wei, Chaoqun; Sun, Liyao; Liu, Huirui; Zhang, Jiayue; Jia-bo, Luo; Yu, Xin; He, Jie; Ge, Heng; Liu, Ping

doi:10.1016/j.biopha.2022.114048

Cited by 65 publications

(24 citation statements)

References 57 publications

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“… Fang et al (2022) demonstrated that SIRT6 overexpression could reverse the decreased levels of GPX4, SLC7A11, and GSH and reduce the cellular accumulation of MDA and ROS to inhibit ferroptosis, ultimately restoring bone formation and angiogenesis and relieving femoral head necrosis. Mi et al demonstrated that melatonin inhibited ferroptosis in rat lens epithelial cells through SIRT6/p-NRF2/GPX4 and SIRT6/NCOA4/FTH1 pathways, neutralized lipid peroxidation toxicity, and delayed the formation of cataract caused by ultraviolet rays exposure ( Mi et al, 2023 ). In addition to direct evidence, SIRT6 can also modulate ferroptosis-associated genes, which indirectly demonstrates that SIRT6 can regulate ferroptosis.…”

Section: Roles Of Sirtuins In Ferroptosismentioning

confidence: 99%

The roles of sirtuins in ferroptosis

et al. 2023

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Ferroptosis represents a novel non-apoptotic form of regulated cell death that is driven by iron-dependent lipid peroxidation and plays vital roles in various diseases including cardiovascular diseases, neurodegenerative disorders and cancers. Plenty of iron metabolism-related proteins, regulators of lipid peroxidation, and oxidative stress-related molecules are engaged in ferroptosis and can regulate this complex biological process. Sirtuins have broad functional significance and are targets of many drugs in the clinic. Recently, a growing number of studies have revealed that sirtuins can participate in the occurrence of ferroptosis by affecting many aspects such as redox balance, iron metabolism, and lipid metabolism. This article reviewed the studies on the roles of sirtuins in ferroptosis and the related molecular mechanisms, highlighting valuable targets for the prevention and treatment of ferroptosis-associated diseases.

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Section: Roles Of Sirtuins In Ferroptosismentioning

confidence: 99%

The roles of sirtuins in ferroptosis

et al. 2023

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“…20 Melatonin also regulates ferroptosis, a form of cell death, in various diseases. [21][22][23] Whether melatonin or MT1 can prevent ferroptosis in PD is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Altered microglial metabolism and increased neuroinflammation in PD are associated with MT1 deficiency 20 . Melatonin also regulates ferroptosis, a form of cell death, in various diseases 21–23 . Whether melatonin or MT1 can prevent ferroptosis in PD is unknown.…”

Section: Introductionmentioning

confidence: 99%

Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho‐1/Gpx4 pathway to prevent α‐synuclein‐induced ferroptosis in Parkinson's disease

Lv,

Tao,

Yao

et al. 2024

Journal of Pineal Research

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α‐synuclein (α‐syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α‐syn and ferroptosis in PD. Here, we used α‐syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α‐syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α‐syn PFF‐induced intracellular α‐syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α‐syn‐induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.

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“…Melatonin is believed to have antioxidant and anti‐inflammatory effects, which can alleviate oxidative stress and inflammatory responses caused by stroke 10 . In addition, melatonin can also regulate iron metabolism and transport processes, inhibit iron accumulation and excessive release, thereby reducing iron‐induced cytotoxicity 11,12 . Research has also found that melatonin can alleviate nerve cell damage caused by stroke through regulating cell apoptosis and neurotransmitter release pathways 9 .…”

Section: Introductionmentioning

confidence: 99%

“…10 In addition, melatonin can also regulate iron metabolism and transport processes, inhibit iron accumulation and excessive release, thereby reducing iron-induced cytotoxicity. 11,12 Research has also found that melatonin can alleviate nerve cell damage caused by stroke through regulating cell apoptosis and neurotransmitter release pathways. 9 Although more research is needed to understand the role of melatonin in stroke and iron-mediated death regulation, the available evidence indicates that melatonin may have potential therapeutic and preventive effects on stroke.…”

mentioning

confidence: 99%

Melatonin alleviates ischemic stroke by inhibiting ferroptosis through the CYP1B1/ACSL4 pathway

Sun,

Jin,

et al. 2024

Environmental Toxicology

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This study utilized middle cerebral artery occlusion (MCAO) mouse models and HT‐22 cell oxygen and glucose deprivation/reoxygenation (OGD/R) models to investigate the therapeutic effects of melatonin on ischemic brain injury. In the experiments, MCAO mice were treated with 5 and 10 mg/kg doses of melatonin, and H‐T22 cells underwent OGD/R treatment and were administered different concentrations of melatonin. The results showed that melatonin significantly reduced ischemic brain area, neural damage, cerebral edema, and neuronal apoptosis in MCAO mice. In the HT‐22 cell model, melatonin also improved cell proliferation ability, reduced apoptosis, and ROS production. Further mechanistic studies found that melatonin exerts protective effects by inhibiting ferroptosis, an iron‐dependent form of regulated cell death, through regulation of the ACSL4/CYP1B1 pathway. In MCAO mice, melatonin decreased lipid peroxidation, ROS production, and ACSL4 protein expression. Overexpression of CYP1B1 increased ACSL4 ubiquitination and degradation, thereby increasing cell tolerance to ferroptosis, reducing ACSL4 protein levels, and decreasing ROS production. CYP1B1 knockdown obtained opposite results. The CYP1B1 metabolite 20‐HETE induces expression of the E3 ubiquitin ligase FBXO10 by activating PKC signaling, which promotes ACSL4 degradation. In the OGD/R cell model, inhibition of CYP1B1 expression reversed the therapeutic effects of melatonin. In summary, this study demonstrates that melatonin protects the brain from ischemic injury by inhibiting ferroptosis through regulation of the ACSL4/CYP1B1 pathway, providing evidence for new therapeutic targets for ischemic brain injury.

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

Cited by 65 publications

References 57 publications

The roles of sirtuins in ferroptosis

The roles of sirtuins in ferroptosis

Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho‐1/Gpx4 pathway to prevent α‐synuclein‐induced ferroptosis in Parkinson's disease

Melatonin alleviates ischemic stroke by inhibiting ferroptosis through the CYP1B1/ACSL4 pathway

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