Emerging regulated cell death (cuproptosis, disulfidptosis, and PANoptosis) in ischemic stroke: research progress and translational prospects
TL;DR
These three death modalities exhibit marked cell-type heterogeneity across neurons, microglia, astrocytes, and endothelial cells within the neurovascular unit, and converge on shared hubs of oxidative stress, mitochondrial dysfunction, and inflammatory signaling, forming a complex inter-pathway crosstalk network.
Abstract
Ischemic stroke (IS) is one of the leading causes of disability and mortality worldwide. Its pathological mechanisms involve complex cascades including energy metabolism failure, excitotoxicity, oxidative stress, neuroinflammation, and multiple forms of regulated cell death (RCD). In recent years, cuproptosis, disulfidptosis, and PANoptosis, as three emerging RCD modalities, have attracted increasing attention in ischemic brain injury. Cuproptosis is triggered by copper overload and leads to proteotoxic stress via abnormal oligomerization of lipoylated mitochondrial proteins. Disulfidptosis occurs under glucose deprivation combined with high SLC7A11 expression, driven by NADPH depletion and intracellular disulfide stress that collapses the actin cytoskeleton. PANoptosis integrates pyroptosis, apoptosis, and necroptosis through the PANoptosome—a multiprotein platform assembled by innate immune sensors (ZBP1, AIM2, NLRP3) together with adaptor proteins (ASC, FADD) and effectors (caspase-1/8, RIPK3, MLKL, GSDMD)—leading to simultaneous execution of all three death programs and amplified neuroinflammatory injury. These three death modalities exhibit marked cell-type heterogeneity across neurons, microglia, astrocytes, and endothelial cells within the neurovascular unit, and converge on shared hubs of oxidative stress, mitochondrial dysfunction, and inflammatory signaling, forming a complex inter-pathway crosstalk network. This review systematically summarizes the molecular mechanisms, cellular specificity, spatiotemporal dynamics, and inter-pathway crosstalk of these three emerging RCDs in ischemic stroke, and discusses the clinical translational prospects of targeted and combination intervention strategies—including a stage-classified analysis of therapeutic candidates from preclinical to clinical development—providing a theoretical basis for the design of novel neuroprotective agents.