Melatonin Alleviates Retinal Ischemia–Reperfusion Injury by Inhibiting p53–Mediated Ferroptosis

Abstract

Retinal ischemia–reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detailed mechanisms underlying RGC death caused by RIR have not yet been clearly elucidated, and effective treatments are lacking. Ferroptosis is a recently defined form of programmed cell death that is closely related to organ injury. Melatonin (MT) is a promising neuroprotective agent, but its effects on RIR injury remain unclear. In this study, murine models of acute ocular hypertension and oxygen and glucose deprivation/reoxygenation (OGD/R) model were adopted to simulate retinal ischemia. MT alleviated retinal damage and RGC death in RIR mice, significantly attenuating RIR–induced ferroptosis. Furthermore, MT reduced the expression of p53, a master regulator of ferroptosis pathways, and the upregulation of p53 promoted ferroptosis and largely abolished the neuroprotective effects of MT. Mechanistically, the overexpression (OE) of p53 suppressed the expression of the solute carrier family 7 member 11 (Slc7a11), which was accompanied by increased 12–lipoxygenase (Alox12) expression, triggering retinal ferroptosis. Moreover, MT–ameliorated apoptosis, neuroinflammation and microglial activation were observed. In summary, MT conferred neuroprotection against RIR injury by inhibiting p53–mediated ferroptosis. These findings indicate that MT is a retina–specific ferroptosis inhibitor and a promising therapeutic agent for retinal neuroprotection.

Hypoxia Aggravates Neuron Ferroptosis in Early Brain Injury Following Subarachnoid Hemorrhage via NCOA4-Meditated Ferritinophagy

“…The present article also possesses certain limitations. The process of iron metabolism during EBI is intricate, encompassing not only iron storage but also absorption and excretion, necessitating further investigation [55][56][57]. Simultaneously, further investigation is required to explore the metabolism of other cells such as microglia and astrocytes during EBI.…”

Ferroptosis inhibitors: past, present and future

“…MLT was found to inhibit ferroptosis in subarachnoid haemorrhage-mediated neuronal injury by activating genes such as Nrf2 and Heme oxygenase-1 (HO-1) ( Ma et al, 2023 ). Furthermore, MLT alleviates retinal damage and retinal ganglion cells (RGC) death by inhibiting p53-mediated ferroptosis ( Zhang et al, 2023 ). Thus MTL is expected to be a potential therapeutic agent for the treatment of ferroptosis-mediated diseases.…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“…Melatonin, an indole hormone that contributes to neuroprotection, exerts a neuroprotective effect by inhibiting ferroptosis. 584 – 587 A recent study showed that melatonin ameliorates neurological deficits by inhibiting neuroinflammation and ferroptosis via MT2/IL-33/ferritin H signaling in TBI. 588 Melatonin improves brain function in mice after TBI by inhibiting ferroptosis and ER stress by reducing the expression of circPtpn14 (mmu_circ_0000130), which sponges miR-351-5p to downregulate 5-LOX.…”