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.
Jianhui Li, Annan Liu, Wei Gao et al.· Molecular Medicine Reports· 0 citations
Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.
Xinkai Wu, Qiuyan Ye, Min Zi et al.· Molecular and cellular neuro...· 0 citations
