Alternative Splicing in Central Nervous System: Molecular Mechanisms and Pathophysiological Roles

Central Nervous System (CNS) injuries represent a major cause of long-term neurological disability and mortality worldwide, encompassing stroke, Traumatic Brain Injury (TBI), and Spinal Cord Injury (SCI). Despite distinct etiologies, these conditions share convergent secondary injury processes that critically shape disease progression and long-term outcomes. Alternative Splicing (AS), a unique post-transcriptional regulatory mechanism, has recently been recognized to play crucial roles in brain injury, to be dynamically activated following central nervous system (CNS) injury, and to contribute to the sustained remodeling of gene expression programs during the subacute and chronic phases. In this review, we summarize recent advances in understanding how injury-induced AS alterations influence post-injury pathophysiology across stroke, TBI, and SCI, with particular emphasis on inflammation, apoptosis, and tissue remodeling. Furthermore, we discuss how pathwaylevel regulation, such as NF-κB-mediated inflammatory cascades, caspase-dependent apoptotic signaling, and neurotrophic factor-driven recovery processes, can be either exacerbated or alleviated through AS-dependent isoform switching. Finally, we discuss current limitations in linking splicing alterations to functional outcomes and outline future directions that integrate transcriptomic resolution with mechanistic validation, refining the conceptual framework of AS as a regulatory layer shaping long-term CNS injury responses.