Molecular mechanisms and therapeutic strategies for ferroptosis and cuproptosis in ischemic stroke

Abstract

Ischemic stroke, as one of the most severe and prevalent neurological disorders, poses a significant threat to the health and quality of life of affected individuals. Stemming from the obstruction of blood flow, ischemic stroke, leads to cerebral tissue hypoxia and ischemia, instigating a cascade of pathophysiological changes that markedly exacerbate neuronal damage and may even culminate in cell death. In recent years, emerging research has increasingly focused on novel cell death mechanisms such as ferroptosis and cuproptosis. Mounting evidence underscores the independent roles of ferroptosis and cuproptosis in ischemic stroke. This review aims to elucidate potential cross-regulatory mechanisms between ferroptosis and cuproptosis, exploring their regulatory roles in ischemic stroke. The objective is to provide targeted therapeutic intervention strategies.

Keywords: Ferroptosis, Cuproptosis; Ischemic stroke; Mechanism.

Fig. 1

Iron regulatory proteins like transferrin are critical in iron-induced cell death (Cardona et al., 2023). Ischemic stroke disrupts their regulation, causing iron accumulation and abnormal distribution, activating apoptotic pathways. Excess oxygen radicals and iron damage mitochondrial membranes, releasing apoptotic signals such as cytochrome C, activating caspases, and inducing cell apoptosis.

Fig. 2

Copper imbalance disrupts mitochondrial function, impairing TCA cycle enzymes and mitochondrial membranes, increasing oxidative damage and cell death. As a cofactor for cytochrome c oxidase and superoxide dismutase (SOD), copper imbalance reduces antioxidant defenses, exacerbating oxidative stress.