The dual role of endoplasmic reticulum stress in cerebral ischemia: from adaptive protection to apoptotic induction

Endoplasmic reticulum (ER) stress is a critical determinant of neuronal fate following cerebral ischemia, functioning as both an adaptive survival mechanism and a potent inducer of cell death. Ischemic insult and subsequent reperfusion profoundly disrupt ER proteostasis, calcium homeostasis, and redox balance, leading to activation of the unfolded protein response (UPR). While transient UPR activation promotes neuronal survival by attenuating protein synthesis, enhancing protein folding capacity, and facilitating degradation of misfolded proteins, sustained or excessive ER stress converts this adaptive response into a pro-apoptotic program that accelerates neuronal loss. This review systematically summarizes the molecular basis of ER stress in cerebral ischemia, with a particular focus on the spatiotemporal regulation of the three canonical UPR branches-PERK, IRE1α, and ATF6. We highlight how these pathways initially coordinate cytoprotective responses but subsequently drive apoptosis through CHOP induction, mitochondrial dysfunction, oxidative stress, and inflammatory signaling. The reciprocal amplification between ER stress, reactive oxygen species, and inflammatory cascades establishes a pathological network that propagates ischemic brain injury. Importantly, accumulating evidence indicates that therapeutic modulation of ER stress must be precisely timed and pathway-specific. Selectively enhancing adaptive UPR signaling while suppressing maladaptive PERK-CHOP and IRE1α-JNK pathways represents a promising strategy for neuroprotection. By integrating recent mechanistic and translational studies, this review positions ER stress as a central regulatory hub in ischemic stroke and provides a framework for the development of targeted interventions aimed at improving neurological recovery.