Mitochondrial dysfunction-driven ferroptosis in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic strategies (Review)

Abstract

Ischemic stroke remains a leading cause of mortality and disability worldwide. Although vascular recanalization is essential for salvaging the ischemic penumbra, subsequent reperfusion may initiate a cascade of secondary brain injury, a pathological process referred to as cerebral ischemia-reperfusion injury (CIRI). Ferroptosis, an iron-dependent form of programmed cell death characterized by the excessive accumulation of lipid peroxides and membrane damage, has emerged as a critical driver of neuronal death in CIRI. Growing evidence supports mitochondrial dysfunction as not only a downstream outcome of bioenergetic failure, but also a central regulatory node within the ferroptotic cascade. The present review systematically summarizes how mitochondrial dysfunction increases neuronal susceptibility to ferroptosis across the pathophysiological progression of CIRI, with a particular focus on the underlying mechanisms. Specifically, a multidimensional pathological network composed of multiple mitochondrial abnormalities, including mitochondrial reactive oxygen species bursts, Ca2+ overload and disruption of the mitochondrial quality control system, encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy, synergistically amplifies lipid peroxidation and drives neuronal ferroptosis. Finally, advances and future perspectives regarding mitochondria-centered therapeutic strategies are highlighted, offering novel insights into the development of targeted neuroprotective interventions against CIRI-induced ferroptosis.