Mechanism by which non-apoptotic regulated cell death induces neuronal injury in ischemic stroke

Abstract

BACKGROUND: In recent years, the involvement of non-apoptotic regulated cell death in the development of ischemic stroke has become a research hotspot. OBJECTIVE: To summarize the roles and action mechanisms of non-apoptotic regulated cell death subroutines such as autophagy, ferroptosis, cuproptosis, disulfidptosis, necroptosis, and pyroptosis in the neuronal damage caused by ischemic stroke. METHODS: Relevant literature on non-apoptotic regulated cell death and ischemic stroke was retrieved from the China National Knowledge Infrastructure and PubMed databases. The search terms included "ischemic stroke, regulated cell death, autophagy, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition-driven necrosis, neutrophil extracellular trap-related death, lysosome-dependent cell death, immunogenic cell death, anoikis" in English and corresponding Chinese terms. Based on inclusion criteria, 176 articles were finally included for analysis and summary. RESULTS AND CONCLUSION: The regulatory mechanisms of non-apoptotic regulated cell death mainly include autophagy, ferroptosis, anoikis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, oxeiptosis, alkaliptosis, parthanatos, mitochondrial permeability transition-driven necrosis, neutrophil extracellular trap-related death, lysosome-dependent cell death, and immunogenic cell death. Autophagy plays a dual regulatory role in neuronal injury after ischemic stroke: under ischemic conditions, autophagy exerts a neuroprotective effect, whereas excessive autophagy during reperfusion can lead to neuronal death. Ferroptosis can aggravate neuronal injury in ischemic stroke through iron overload and lipid peroxidation. Cuproptosis can regulate glutathione-induced ferroptosis by modulating the protein ferredoxin 1. There is partial crosstalk between disulfidptosis and ferroptosis; under glucose deprivation, upregulation of solute carrier family 7 member 11 consumes NADPH, leading to abnormal accumulation of disulfide compounds and promoting disulfidptosis in neurons. Mixed lineage kinase domain-like pseudokinase, a key participant in necroptosis, is also associated with activation of the pyroptosis-related protein NLRP3 inflammasome, further promoting neuronal pyroptosis during necroptosis in ischemic stroke. Neutrophil extracellular trap-related death in ischemic stroke is mainly caused by citrullination, stress-triggered neutrophil extracellular trap formation, and inflammatory responses mediated by release of various cytotoxic proteases. Other emerging subtypes such as immunogenic cell death cause neuronal damage in ischemic stroke through various specific mechanisms.

1. Introduction

Stroke is an acute cerebrovascular disease caused by sudden blockage of blood flow or rupture of blood vessels in brain tissue, leading to brain damage. Stroke includes hemorrhagic stroke and ischemic stroke, with ischemic stroke accounting for 87% of all stroke cases [1]. It is the second leading cause of death globally and a major cause of long-term disability [2]. After stroke, blood components infiltrate the brain parenchyma, and factors such as lysed cell debris, ischemia, and hypoxia typically increase blood-brain barrier permeability, inflammatory responses, and brain edema, ultimately leading to neuronal death. In untreated stroke patients, approximately 1.9 million neurons are destroyed per minute, and 120 million neurons are lost per hour [3].

Currently, the introduction of effective reperfusion strategies, including intravenous thrombolysis and endovascular thrombectomy, has revolutionized the treatment of acute ischemic stroke by restoring blood flow to the ischemic penumbra before irreversible tissue damage occurs, thereby improving patient outcomes. However, despite the significant efficacy of thrombolysis, the narrow therapeutic window often results in many patients missing the optimal time for thrombolysis and vascular treatment, leading to secondary injury [4]. Therefore, there is an urgent need to develop new therapeutic targets for the treatment and prognosis optimization of ischemic stroke.

Regulated cell death (RCD) is a controlled form of cell death [5]. Based on distinct morphological, molecular, and functional characteristics, RCD subroutines can be classified into apoptotic and non-apoptotic cell death, playing important roles in maintaining homeostasis, promoting development, and regulating immunity [6]. Apoptotic RCD includes extrinsic, mitochondrial intrinsic, and endoplasmic reticulum stress pathways. Non-apoptotic RCD mechanisms mainly include autophagy, ferroptosis, anoikis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, oxeiptosis, alkaliptosis, parthanatos, mitochondrial permeability transition-driven necrosis, neutrophil extracellular trap-related death, lysosome-dependent cell death, and immunogenic cell death.