MBNL1-mediated alternative splicing in cancer: underlying mechanism, isoform regulation, and translational perspectives

Alternative splicing (AS) is a major mechanism that expands proteomic diversity and fine-tunes gene expression in eukaryotic cells. Its dysregulation is now recognized as a hallmark of cancer and contributes to tumor initiation, progression, metastasis, and therapeutic resistance. Muscleblind-like splicing regulator 1 (MBNL1) is a highly conserved RNA-binding protein (RBP) that controls AS, RNA stability, and other aspects of transcript processing. Increasing evidence indicates that MBNL1 expression, isoform composition, and subcellular localization are frequently altered in multiple cancer types. Through these changes, MBNL1 reshapes the splicing programs of cancer-related genes and exerts context-dependent tumor-suppressive or tumor-supportive effects. This review summarizes the structure and biological functions of MBNL1, the major mechanisms through which it regulates cancer-associated AS, its expression and isoform-specific features across different tumor types, and emerging therapeutic strategies targeting MBNL1 and its downstream splicing network. Current challenges and future directions are also discussed. Overall, MBNL1 represents a promising splicing regulator with potential value for biomarker development and precision cancer therapy.