Ubiquitination in ischemic stroke: Molecular mechanisms and therapeutic implications

Ischemic stroke is an acute cerebrovascular syndrome caused by a precipitous reduction or interruption of cerebral blood flow. Its pathophysiology involves the sequential activation of energy failure, excitotoxicity, oxidative stress, neuroinflammation, and multiple cell death programs. As a pivotal post-translational modification, ubiquitination deeply participates in post-ischemic remodeling of proteostasis by controlling the stability, subcellular localization, and signaling activity of substrate proteins. Accumulating evidence indicates that the ubiquitin-proteasome system (UPS) and deubiquitinase networks undergo pronounced time- and cell type-dependent changes after ischemic stroke and exert bidirectional effects on cell death, neuroinflammation, mitochondrial quality control, synaptic remodeling, and blood-brain barrier homeostasis. On the one hand, specific E3 ubiquitin ligases or deubiquitinases can restrain inflammatory amplification, facilitate the clearance of damaged proteins, and preserve mitochondrial homeostasis. On the other hand, aberrant or imbalanced ubiquitination can exacerbate oxidative injury, mitochondrial dysfunction, and neuronal loss. Although targeting ubiquitination pathways has shown therapeutic promise, substantial heterogeneity across ubiquitin chain types, cell populations, and disease stages continues to constrain clinical translation. This review therefore summarizes the global response, molecular mechanisms, and interventional prospects of the ubiquitination network after ischemic stroke, with the aim of providing a theoretical basis for precision therapies targeting the UPS/DUB axis.