Mechanisms of ubiquitination in central nervous system injury and potential therapeutic targets.

Ubiquitination is a highly conserved and reversible post-translational modification that regulates protein stability, localization, activity, and intracellular signaling through the coordinated actions of the ubiquitin-proteasome system. In recent years, increasing evidence has highlighted the critical role of ubiquitination in maintaining central nervous system proteostasis and regulating pathological responses following central nervous system injury. This review comprehensively summarizes recent advances in research on ubiquitination in traumatic brain injury, spinal cord injury, stroke, and central nervous system infections, with particular emphasis on its involvement in secondary injury and subsequent neural repair. The mechanisms by which ubiquitination and deubiquitination regulate neuroinflammation, oxidative stress, mitochondrial dysfunction, blood-brain barrier integrity, and programmed cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis, are highlighted. Disease-specific ubiquitination patterns and their contributions to vascular repair, neural stem cell activation, axonal regeneration, and functional recovery are also discussed. Furthermore, emerging therapeutic strategies targeting key ubiquitin-system enzymes, as well as nanotechnology- and artificial intelligence-enabled approaches for precise modulation of ubiquitin-dependent signaling, are summarized and their therapeutic potential is explored. Although promising findings have been obtained from cellular and animal models, the cell-type-, temporal-, and disease-context-specific nature of ubiquitin signaling, substrate selectivity, and distinct ubiquitin-chain topologies remain major barriers to clinical translation. Further studies are therefore needed to elucidate the spatiotemporal dynamics of ubiquitination and identify context-specific therapeutic windows. Overall, ubiquitination represents a central regulatory network connecting proteostasis, neuroinflammation, cell death, and neural repair, providing a promising therapeutic approach for improving neurological outcomes after central nervous system injury.