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

Mitophagy: a regulator and therapeutic target in cerebral ischemia/reperfusion injury.

Cerebral ischemia/reperfusion (I/R) injury refers to the exacerbation of tissue damage following the restoration of blood flow to ischemic brain regions. This condition remains a major challenge in the clinical management of ischemic stroke due to limited therapeutic options. At present, no approved drugs specifically target cerebral I/R injury. Multiple mechanisms contribute to its pathogenesis, with mitochondrial dysfunction playing a central role. During cerebral I/R injury, mitochondria generate excessive reactive oxygen species (ROS), leading to impaired mitochondrial function and further tissue damage. In addition, mitochondrial calcium overload triggers neuronal apoptosis, which promotes disease progression. Given the critical role of mitochondrial dysfunction, preservation of mitochondrial homeostasis may attenuate cerebral I/R injury. Mitophagy, a selective process that removes damaged mitochondria, has been shown to mitigate cerebral I/R injury by limiting the release of harmful mitochondrial-derived factors. Therefore, mitophagy represents a potential therapeutic target for maintaining mitochondrial homeostasis in cerebral I/R injury treatment. This review summarizes the molecular regulation of mitophagy, its role in cerebral I/R injury, and current therapeutic strategies aimed at modulating mitophagy.

Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences

Intracerebral hemorrhage (ICH) carries high rates of disability and mortality, with a poor prognosis largely attributable to secondary brain injury (SBI). Mitochondria, a central hub for cellular redox regulation and energy metabolism, are not only affected by SBI but can also, once dysfunctional, initiate and exacerbate SBI. In this review, we classify post-ICH mitochondrial dysfunction into three major categories: excessive accumulation of mitochondrial reactive oxygen species, dysregulation of energy metabolism, and dysregulation of mitochondrial quantity and quality control. We delineate the molecular mechanisms and pathological consequences of each. Furthermore, given the extensive crosstalk between mitochondrial dysfunction and diverse forms of cell death in ICH (e.g., apoptosis, necrosis, necroptosis, ferroptosis, and pyroptosis), we discuss their mechanistic links. Overall, this review proposes a mitochondria-centered framework and emphasizes crosstalk between different types of dysfunction, thereby advancing our understanding of SBI pathophysiology after ICH and providing a systematic perspective on therapeutic strategies aimed at restoring mitochondrial homeostasis.

Targeting ferroptosis and oxidative stress crosstalk: a new frontier in stroke neuroprotection

HIF-1α in ischemic stroke: context-dependent roles in ferroptosis and neurovascular repair

Stroke remains a leading cause of death and long-term disability worldwide, and effective strategies to limit ischemic injury and promote post-stroke tissue repair remain urgently needed. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron accumulation and lipid peroxidation, has emerged as an important mechanism contributing to neuronal and neurovascular injury after ischemic stroke. Hypoxia-inducible factor-1α (HIF-1α), a central regulator of cellular responses to hypoxia, is closely involved in both ferroptotic injury and post-stroke neurovascular repair. In this review, we summarize current evidence on the context-dependent role of HIF-1α in ferroptosis and neurovascular repair after ischemic stroke. HIF-1α regulates ferroptosis through multiple mechanisms, including modulation of iron homeostasis, antioxidant defense, lipid metabolism, and lipid peroxidation. However, its effects are not uniformly protective or detrimental and may vary according to the severity and duration of ischemia, the timing of HIF-1α activation, the metabolic state and cellular context. Beyond ferroptosis, HIF-1α contributes to post-stroke neurovascular repair by regulating angiogenesis and vascular remodeling, blood–brain barrier restoration, neurogenesis, and neuronal remodeling. These findings suggest that HIF-1α may serve as a molecular link between ischemic injury, ferroptosis, and endogenous repair responses. Rather than simply activating or inhibiting HIF-1α, therapeutic strategies that selectively modulate HIF-1α signaling according to the stage and pathological context of ischemic stroke may provide a more rational approach to limiting ferroptotic injury while promoting neurovascular repair.

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.

Curcumin in ischemia–reperfusion injury across multiple organs: A review

Ischemia–reperfusion injury is a secondary pathophysiological process triggered by the restoration of blood flow to ischemic tissues, characterized by a detrimental cascade of oxidative stress, hyperinflammation, and programmed cell death that frequently compromises the function of multiple vital organs, including the heart, brain, liver, and kidneys. This narrative review systematically synthesizes current evidence on the protective efficacy and molecular mechanisms of curcumin, a natural polyphenolic compound, against ischemia–reperfusion injury across major organ systems. Mechanistically, curcumin orchestrates a multitargeted defense by activating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 antioxidant axis, suppressing the nuclear factor kappa-light-chain-enhancer of activated B cells-driven inflammatory storm, and modulating the phosphoinositide 3-kinase/protein kinase B survival pathway. These actions collectively result in the inhibition of reactive oxygen species generation, mitigation of mitochondria-dependent apoptosis, and preservation of microcirculatory integrity. Although curcumin demonstrates significant protective effects across the heart, liver, kidneys, lungs, brain, spinal cord, and intestines by reducing tissue damage markers and ameliorating pathological morphology, its clinical translation remains hindered by the inherent drawbacks of poor water solubility, low oral bioavailability, and rapid metabolic clearance. Future research should prioritize the integration of curcumin with advanced nanocarrier delivery systems and high-resolution spatial transcriptomics to enhance targeted therapeutic efficacy, thereby paving the way for novel clinical strategies against ischemia–reperfusion injury.