Molecular Networks of Cell Death in Ischemic Stroke: From Mechanisms to Interventions.

Abstract

Ischemic stroke involves a complex network of interconnected processes, including bioenergetic failure, excitotoxicity, ionic dyshomeostasis involving Na+, K+, Ca2+, and Cl-, oxidative stress, DNA damage, and neurovascular dysfunction. Apoptosis, necroptosis, pyroptosis, ferroptosis, and parthanatos contribute to experimental ischemic injury with different levels of mechanistic support. Autophagy primarily maintains cellular homeostasis and modulates these pathways. Autophagy-dependent cell death requires separate evidence that the autophagic machinery causes death. These processes operate across the ischemic core and penumbra and evolve during ischemia, reperfusion, and recovery. Their effects extend beyond neurons to microglia, astrocytes, brain microvascular endothelial cells, pericytes, and other neurovascular components. This narrative review evaluates pathway execution, shared molecular nodes, and the spatial and temporal limits of the available evidence. It emphasizes receptor-complex regulation, mitochondrial and lysosomal function, phospholipid peroxidation, DNA damage, and inflammatory signaling as points of convergence. Preclinical interventions are assessed according to their models, molecular endpoints, and functional outcomes. A cell- and stage-specific network perspective supports the development of targeted therapies, while the efficacy and safety of coordinated pathway intervention in patients remain to be established.