Mol Biol Rep. 2026 May 11;53(1):734. doi: 10.1007/s11033-026-11915-7.
ABSTRACT
The pathological condition known as ischemia reperfusion injury (IRI) is characterized by an initial restriction in the amount of blood supply followed by reperfusion which paradoxically aggravates irreversible neuronal damage and cell death. In Central Nervous System, IRI disrupts cytoskeletal integrity, causes dysruption in intracellular calcium homeostasis, and worsens mitochondrial function. Accruing evidence identifies endoplasmic reticulum (ER) stress and dysregulation of the unfolded protein response (UPR) as key contributors to ischemia-induced neurodegeneration. While transient ER stress activates adaptive signaling that supports cell survival, sustained or severe ER stress shifts UPR signaling toward pro-apoptotic pathways involving CHOP induction, calcium overload, mitochondrial dysfunction, and caspase activation. This review critically examines recent advances linking ER stress to neuronal injury following cerebral ischemia and reperfusion, with a particular emphasis on ER-mitochondrial crosstalk and apoptotic signaling. Importantly, we summarize and evaluate emerging therapeutic strategies targeting ER stress pathways including chemical chaperones, UPR modulators, calcium homeostasis regulators, and metabolic interventions-and discuss their neuroprotective potential and translational limitations. By integrating mechanistic insights with therapeutic perspectives, this review highlights ER stress as a promising but complex target for neuroprotection after ischemic injury.
PMID:42113332 | DOI:10.1007/s11033-026-11915-7