Astrocytic Multimodal Programmed Cell Death in Ischemic Stroke: Regulatory Mechanisms and Translational Prospects.

INTRODUCTION

Ischemic stroke remains a leading cause of disability and mortality worldwide. Current neuroprotective treatments predominantly target neurons and fail to address the complex post-ischemic cell death cascades in astrocytes, the most abundant glial cells in the central nervous system, whose multimodal Programmed Cell Death (PCD) directly determines blood-brain barrier integrity, neuroinflammation, and secondary brain injury.

METHODS

The literature on astrocytic PCD in ischemic stroke was systematically reviewed before April 2026, encompassing spatiotemporal dynamics, molecular mechanisms, inter-pathway crosstalk, and translational strategies in preclinical and clinical models.

RESULTS

Astrocytes undergo spatiotemporally regulated multimodal PCD apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic cell death with pronounced regional heterogeneity between ischemic core and penumbra. Single-cell transcriptomic analyses reveal distinct death subpopulations distributed in a brain-region-specific manner. Important molecular switches including iron metabolism, reactive oxygen species, RIPK1, and the p53/NF-κB axis integrate multiple death pathways into a hierarchical crosstalk network. Astrocytic death functions as an important amplifier governing neurovascular unit integrity.

DISCUSSION: A precision therapy strategy was proposed grounded in dominant astrocytic death subtypes, incorporating stage-specific targeting, nanotechnology-enabled drug delivery, and astrocyte reprogramming toward neuroprotective phenotypes. Translational challenges include interspecies differences, incomplete spatiotemporal molecular mapping, and absence of clinically validated biomarkers. Future integration of multiomics and humanized models is needed to bridge the preclinical-clinical gap.

CONCLUSION

Astrocytic multimodal PCD provides novel mechanistic insights and translational targets for neurovascular protection after ischemic stroke, facilitating the paradigm shift from neurocentric neuroprotection to neuron-glia synergistic therapy.