Ferroptosis contributes to hypoxic–ischemic brain injury in neonatal rats: Role of the SIRT1/Nrf2/GPx4 signaling pathway

Abstract

Aims Hypoxic–ischemic brain injury (HIBI) often results in cognitive impairments. Herein, we investigated the roles of ferroptosis in HIBI and the underlying signaling pathways. Methods Ferrostatin‐1 (Fer‐1) or resveratrol (Res) treatments were administered intracerebroventricularly 30 min before HIBI in 7‐day‐old rats. Glutathione peroxidase 4 (GPx4) expression, malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, and the expression of silent information regulator factor 2‐related enzyme 1 (SIRT1) and nuclear factor erythroid‐2‐related factor 2 (Nrf2) were measured after HIBI. Additionally, the weight ratio of left/right hemisphere, brain morphology, Nissl staining, and the Morris water maze test were conducted to estimate brain damage. Results At 24‐h post‐HIBI, GPx4 expression was decreased, and MDA concentration and iron content were increased in the hippocampus. HIBI led to mitochondrial atrophy, brain atrophy/damage, and resultant learning and memory impairments, which were alleviated by Fer‐1‐mediated inhibition of ferroptosis. Furthermore, Res‐mediated SIRT1 upregulation increased Nrf2 and GPx4 expression, thereby attenuating ferroptosis, reducing brain atrophy/damage, and improving learning and memory abilities. Conclusion The results demonstrated that during HIBI, ferroptosis occurs via the SIRT1/Nrf2/GPx4 signaling pathway, suggesting it as a potential therapeutic target for inhibiting ferroptosis and ameliorating HIBI‐induced cognitive impairments.

Echinocystic acid alleviated hypoxic-ischemic brain damage in neonatal mice by activating the PI3K/Akt/Nrf2 signaling pathway

“…Second, the pathogenesis of neonatal HIE is complicated; we only focused on oxidative stress and apoptosis, and other pathological factors, such as inflammation, mitochondrial dysfunction and excitotoxicity, might be involved. Finally, the expression of Nrf2 can be enhanced by the activation of silent information regulator 2-related enzyme 1 (SIRT1), ameliorating HIBD-induced ferroptosis and exerting a neuroprotective effect ( Li C. et al, 2022 ). Whether EA can alleviate HIBD by inhibiting ferroptosis through the SIRT1/Nrf2 signaling pathway needs to be further explored.…”

Narrative review of ferroptosis in obesity

“…Silent information regulator factor 2-related enzyme 1 (SIRT1)/Nrf2/GPX4 signalling pathway as a potential therapeutic target for inhibiting ferroptosis. 60 SIRT1 is a nicotinamide adenine dinucleotide-dependent histone deacetylase, promote longevity and protect individual organisms from age-associated diseases. 61 In additional, sphingosine 1-phosphate (S1P) alleviates radiation-induced ferroptosis in ovarian granulosa cells by upregulating GPX4.…”

“…Modulating GPX4 activity and expression is also a potential strategy to alleviate ferroptosis. Silent information regulator factor 2‐related enzyme 1 (SIRT1)/Nrf2/GPX4 signalling pathway as a potential therapeutic target for inhibiting ferroptosis 60 . SIRT1 is a nicotinamide adenine dinucleotide‐dependent histone deacetylase, promote longevity and protect individual organisms from age‐associated diseases 61 .…”

Neurodegeneration, Mitochondria, and Antibiotics

“…Iron accumulation and lipid peroxidation in different areas of the brain have been proposed as key disease-causing factors in many neurodegenerative diseases [ 119 ]. Abnormal iron homeostasis generally leads to iron overload, which destroys proteins and lipids via Fenton reactions [ 120 , 121 ]. Excessive iron accumulation and lipid peroxidation are frequently accompanied by oxidative stress, mitochondrial dysfunction, increased lipofuscin granules, and autophagy dysregulation [ 22 , 120 , 122 ].…”