Iron-driven secondary injury after intracranial hemorrhage: mitochondrial dysfunction and ferroptosis

Intracranial hemorrhage is a devastating neurological condition associated with high mortality and limited therapeutic options beyond surgical management. Increasing evidence identifies iron released from hemoglobin degradation as a central mediator of secondary brain injury and a critical trigger for chronic neurodegenerative processes that persist long after the acute hemorrhagic event across hemorrhage subtypes, including intracerebral, subarachnoid, intraventricular, and subdural hemorrhage. Excess iron drives oxidative stress through reactive oxygen species generation and lipid peroxidation, disrupts blood–brain barrier integrity, and induces profound mitochondrial dysfunction. These pathological processes converge on ferroptosis, an iron-dependent form of regulated cell death characterized by glutathione peroxidase 4 (GPX4) inactivation, lipid peroxidation, and distinctive mitochondrial structural abnormalities. Experimental and clinical studies consistently demonstrate biomarkers of iron overload, oxidative damage, mitochondrial injury, and ferroptotic signaling in hemorrhagic brain injury. Iron-mediated mechanisms also contribute to delayed complications, including neuroinflammation, white matter injury, and delayed cerebral ischemia, as well as progressive cognitive impairment, thereby extending injury beyond the acute phase and promoting sustained neuronal vulnerability. This review explores current evidence linking iron accumulation, mitochondrial dysfunction, and ferroptosis across intracranial hemorrhage subtypes and highlights emerging therapeutic strategies targeting iron chelation, ferroptosis inhibition, enhancement of endogenous antioxidant defenses, and mitochondrial protection. Targeting this interconnected pathological axis represents a promising strategy for the development of disease-modifying therapies aimed at mitigating secondary brain injury and limiting long-term neurobiological remodeling and improving neurological outcomes following intracranial hemorrhage.