The redox paradox in neurological disorders: balancing cytoprotection, ferroptosis, and therapeutic targeting.

Abstract

Neurological disorders, including ischaemic and haemorrhagic stroke, traumatic brain injury, and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a major global health burden. Despite diverse etiologies, these conditions share common pathological mechanisms driven by oxidative stress, neuroinflammation, mitochondrial dysfunction, iron dysregulation, and secondary neuronal injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade and its downstream target heme oxygenase-1 (HO-1) are master regulators of cellular redox homeostasis. HO-1 plays a pivotal yet dichotomous role: its products biliverdin/bilirubin and carbon monoxide exert antioxidant, anti-inflammatory, and anti-apoptotic effects, whereas excessive HO-1 induction can exacerbate iron-mediated oxidative injury and ferroptosis through the release of redox-active ferrous iron. Rather than cataloguing protective studies, this review builds a contextual framework that specifies when HO-1 activation is protective versus detrimental, organised around three converging determinants: cell-type specificity, iron-handling capacity, and disease stage. We extend this framework to the often-overlooked dimensions of sex, age, and model heterogeneity, and use it to interrogate conflicting findings across the literature. We further dissect how Nrf2/HO-1 regulates ferroptosis through the GPX4-ACSL4-SLC7A11 axis, critically appraise the largely unexamined relationship between Nrf2 and the parallel FSP1/CoQ10, GCH1/BH4, and DHODH defence systems, and distil lessons from clinical trials of Nrf2 activators. The goal is an analytical account that identifies where the evidence is robust, where it is contradictory, and where the principal research gaps lie.

Key Findings

• Nrf2 and its downstream target HO-1 are master regulators of cellular redox homeostasis in neurological disorders.
• HO-1 has a dual role, providing antioxidant and anti-inflammatory effects but potentially exacerbating iron-mediated oxidative injury and ferroptosis when excessively induced.
• The protective versus detrimental effects of HO-1 depend on cell-type specificity, iron-handling capacity, disease stage, as well as factors like sex, age, and model heterogeneity.

Clinical Significance

Citation

Premchandani Tanvi, Qutub Mohammad, Thave Tejaswiniet al.. The redox paradox in neurological disorders: balancing cytoprotection, ferroptosis, and therapeutic targeting. Brain research. 2026-Sep-05.