Alternative splicing: hallmark and therapeutic opportunity in metabolic liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading cause of chronic liver disease worldwide, with fibrosis recognized as the main prognostic factor and therapeutic target. While early-stage fibrosis is reversible, advanced fibrosis poses a significant clinical challenge due to limited treatment options, highlighting the need for innovative management strategies. Recent studies have shown that alternative pre-mRNA splicing, a critical mechanism regulating gene expression and protein diversity, plays a fundamental role in the pathogenesis of MAFLD and associated fibrosis. Understanding the complex relationship between alternative splicing and fibrosis progression in MAFLD could pave the way for novel therapeutic approaches and improve clinical outcomes. In this review, we describe the intricate mechanisms of alternative splicing in fibrosis associated with MAFLD. Specifically, we explored the pivotal of splicing factors, and RNA-binding proteins, highlighting their critical interactions with metabolic and epigenetic regulators. Furthermore, we provide an overview of the latest advancements in splicing-based therapeutic strategies and biomarker development. Particular emphasis is placed on the potential application of antisense oligonucleotides for rectifying splicing anomalies, thereby laying the foundation for precision medicine approaches in the treatment of MAFLD-associated fibrosis.