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Cracking the neuronal ferroptosis code: In vitro insights into mechanisms and treatment of stroke

Year: 2025
Type: article
Abstract: Ferroptosis, a non-apoptotic regulated cell death culminating in iron-dependent lipid peroxidation, has rapidly emerged as an additional mechanism of neuronal death after stroke. Yet, despite converging molecular features, such as the collapse of antioxidant systems and oxidation of lipids, the upstream biochemical landscapes that trigger ferroptosis differ across ischemic and hemorrhagic injury. In this review, we examine ferroptosis as an emergent property of redox network failure, where the transcriptional, metabolic, and oxidative circuits that normally sustain neuronal resilience are interrupted. Cells continuously operate within a spectrum of oxidative eustress and distress, balancing reactive species that serve as physiological signals and limiting their ability to inflict irreversible damage. Within this continuum, eustress supports adaptive redox signaling, metabolic coupling, and repair, whereas distress reflects exhaustion of reducing power and a shift toward self-propagative oxidation. Drawing on evidence from our lab and others, we explore how distinct stress inputs drive neurons and glia along this continuum toward ferroptotic collapse following each stroke subtype; much of this work originated within reductionist in vitro ferroptotic models and has since been extended to in vivo models. Understanding ferroptosis after stroke not only as a graded failure of redox homeostasis but also an evolutionarily adapted mechanism to couple neuronal injury to the reparative immune response is essential. Effective neuroprotective strategies will therefore depend on identifying and targeting the context-specific triggers and temporal windows that define each stroke subtype.
DOI: 10.70401/fos.2026.0017
Language: English
Field: Medicine
Open Access status: hybrid
OpenAlex ID: W7127891258
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