Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets

Abstract

Alternative splicing (AS) is an important posttranscriptional process that increases proteomic complexity of eukaryotes. Through the selective inclusion or exclusion of exons, AS fine-tunes gene expression and underpins diverse biological processes. Recent research revealed that AS is controlled not only by spliceosomal components but also by dynamic RNA structures and the spatial compartmentalization of splicing factors within biomolecular condensates formed via liquid–liquid phase separation (LLPS). Nevertheless, a unified framework connecting these mechanistic insights with emerging therapeutic strategies remains lacking. This review systematically integrates current knowledge of AS regulation, encompassing the architecture and dynamics of the core spliceosome, structural RNA elements such as G-quadruplexes, and LLPS-driven condensates exemplified by oncogenic SRSF9 droplets. It further delineates how AS influences cell development, immune modulation, and stress adaptation, while its dysregulation contributes to human pathologies, including SF3B1 mutant cancers, TDP-43-associated neurodegeneration, and cardiovascular disease. We critically appraise therapeutic innovations targeting aberrant splicing, including small molecule spliceosome modulators, antisense oligonucleotides like nusinersen, and CRISPR/dCas13-based RNA editing. By integrating molecular mechanisms with translational advances, this review provides a conceptual framework to accelerate RNA-targeted precision medicine in the era of spatial multiomics and artificial intelligence.

Keywords

alternative splicing / biological functions / diseases / molecular mechanisms / therapeutic targets

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