Comorbid mechanisms of neuroinflammation and astrocytic ferroptosis in neurological disorders: A vicious cycle (Review)

Abstract

Neuroinflammation and astrocytic ferroptosis form a self-reinforcing vicious cycle across multiple neurological disorders, constituting a core pathological mechanism driving the progression of neurodegeneration, stroke, epilepsy, autoimmune encephalopathy. Initial neuroinflammation activates microglia to release pro-inflammatory factors such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α, inducing the transformation of astrocytes into a neurotoxic A1 phenotype, disrupting iron homeostasis, inhibiting the glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant system, activating the NADPH oxidase 4 (NOX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) pathways, and triggering ferroptosis. Damage-associated molecular patterns, [including high mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and mitochondrial DNA] and pro-inflammatory mediators (including reactive oxygen species and lipid peroxidation products) released by ferroptotic cells further activate glial cells and amplify inflammation, establishing a positive feedback loop. Key regulatory nodes include forkhead box (Fox)O1a, nuclear factor (NF)-κB, nuclear factor erythroid 2-related factor 2 (Nrf2), and sirtuin 1 (SIRT1), while mitochondria-endoplasmic reticulum interactions participate in subcellular regulation. Current intervention strategies encompass iron chelation combined with antioxidants, NOX4 inhibition, blockade of A1 phenotype transformation, targeted activation of receptor tyrosine kinases, and blood-brain barrier-targeted drug delivery. However, challenges remain in cell-specific targeting, spatiotemporal dynamic monitoring, and clinical translation. Breaking this vicious cycle may offer a novel neuroprotective therapeutic direction for neurological disorders.