It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within the central nervous system, including oxygen transport, energy metabolism, and the synthesis and catabolism of myelin and neurotransmitters. During brain development, iron is distributed throughout the brain, playing a pivotal role in key processes such as neuronal development, myelination, and neurotransmitter synthesis. In physiological aging, iron can selectively accumulate in specific brain regions, impacting cognitive function and leading to intracellular redox imbalance, mitochondrial dysfunction, and lipid peroxidation, thereby accelerating aging and associated pathologies. Furthermore, brain iron accumulation may be a primary contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Comprehending the role of iron in brain development, aging, and neurodegenerative diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction of abnormal neurological states, and implementing appropriate interventions may be instrumental in preserving normal central nervous system function.

Ferroptosis is a novel regulated cell death characterized by metabolic disorders and iron-dependent oxidative destruction of the lipid bilayer. It is primarily caused by the imbalance of oxidation and anti-oxidation in the body and is precisely regulated by numerous factors and pathways inside and outside the cell. Recent studies have indicated that ferroptosis plays a vital role in the pathophysiological process of multiple systems of the body including the nervous system. Ferroptosis may be closely linked to the occurrence and development of neurodegenerative diseases, strokes, and brain tumors. It may also be involved in the development, maturation, and aging of the nervous system. Therefore, this study aims to investigate ferroptosis’s occurrence and regulatory mechanism and summarize its research progress in the pathogenesis and treatment of neurological diseases. This would allow for novel ideas for basic and clinical research of neurological diseases.

Ferroptosis is an iron-dependent form of regulated cell death, which is driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid peroxidation. Ferroptosis is implicated in various diseases involving neuronal injury. However, the role of ferroptosis in hypoxic-ischemic brain damage (HIBD) has not been elucidated. The objectives of this study were to evaluate whether ferroptosis is involved in hypoxic-ischemic brain damage and its mechanisms through the HIBD model. A 7-day-old male Sprague-Dawley neonatal rat HIBD model was established by blocking the left common carotid artery. Laser speckle contrast imaging, immunohistochemical staining, transmission electron microscopy were used to measure the effects of ferroptosis on HIBD. Brain tissue on the damaged side in the HIBD group showed atrophied, even liquefied, glial cells increased, and blood perfusion was significantly reduced. The HIBD group insult significantly increased reactive oxygen species levels, as well as the protein levels of iron metabolism-related proteins transferrin receptor (TFRC), ferritin heavy chain (FHC), and ferritin light chain (FLC), while reducing the levels of Solute Carrier Family 7 Member 11 (SLC7A11), glutathione (GSH), and GPX4. These changes resulted in diminished cellular antioxidant capacity and mitochondrial damage, causing neuronal ferroptosis in the cerebral cortex. We conclude that ferroptosis plays a role in HIBD in neonatal rats. Ferroptosis-related mechanisms such as abnormalities in iron metabolism, amino acid metabolism, and lipid peroxidation regulation play important roles in HIBD.

Background: Neuroinflammation and oxidative stress, mediated by microglial activation, hinder the development of oligodendrocytes (OLs) and delay myelination in preterm infants, leading to white matter injury (WMI) and long‐term neurodevelopmental sequelae. Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) has been reported to inhibit inflammation and oxidative stress via modulating microglial polarization in various central nervous system diseases. However, the relationship between PPAR‐γ and microglial polarization in neonatal WMI is not well understood. Therefore, this study aimed to elucidate the role and mechanisms of PPAR‐γ in preterm infants affected by WMI.Methods: In this study, an in vivo hypoxia‐ischemia (HI) induced brain WMI neonatal mouse model was established. The mice were administered intraperitoneally with either RSGI or GW9662 to activate or inhibit PPAR‐γ, respectively. Additionally, an in vitro oxygen–glucose deprivation (OGD) cell model was established and pretreated with pcDNA 3.1‐PPAR‐γ or si‐PPAR‐γ to overexpress or silence PPAR‐γ, respectively. The neuroprotective effects of PPAR‐γ were investigated in vivo. Firstly, open field test, novel object recognization test, and beam‐walking test were employed to assess the effects of PPAR‐γ on neurobehavioral recovery. Furthermore, assessment of OLs loss and OL‐maturation disorder, the number of myelinated axons, myelin thickness, synaptic deficit, activation of microglia and astrocyte, and blood–brain barrier (BBB) were used to evaluate the effects of PPAR‐γ on pathological repair. The mechanisms of PPAR‐γ were explored both in vivo and in vitro. Assessment of microglia polarization, inflammatory mediators, reactive oxygen species (ROS), MDA, and antioxidant enzymes was used to evaluate the anti‐inflammatory and antioxidative effects of PPAR‐γ activation. An assessment of HMGB1/NF‐κB and NRF2/KEAP1 signaling pathway was conducted to clarify the mechanisms by which PPAR‐γ influences HI‐induced WMI in neonatal mice.Results: Activation of PPAR‐γ using RSGI significantly mitigated BBB disruption, promoted M2 polarization of microglia, inhibited activation of microglia and astrocytes, promoted OLs development, and enhanced myelination in HI‐induced WMI. Conversely, inhibition of PPAR‐γ using GW9662 further exacerbated the pathologic hallmark of WMI. Neurobehavioral tests revealed that neurological deficits were ameliorated by RSGI, while further aggravated by GW91662. In addition, activation of PPAR‐γ significantly alleviated neuroinflammation and oxidative stress by suppressing HMGB1/NF‐κB signaling pathway and activating NRF2 signaling pathway both in vivo and in vitro. Conversely, inhibition of PPAR‐γ further exacerbated HI or OGD‐induced neuroinflammation, oxidative stress via modulation of the same signaling pathway.Conclusions: Our findings suggest that PPAR‐γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF‐κB and NRF2/KEAP1 signaling pathway, thereby contributing to neuroprotection and amelioration of HI‐induced WMI in neonatal mice.