RNA splicing in cancer cell death regulation: shedding light on the molecular mechanisms and potential clinical applications

Alternative splicing (AS) is a ubiquitous posttranscriptional regulatory mechanism in eukaryotes through which proteins with various structures and functions are produced from a single pre-mRNA. It is performed by the spliceosome and regulated by both cis-acting elements and trans-acting splicing factors. The common modes of regulatory cell death (RCD) include apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis, and dysregulation of these cell death modes can lead to tumorigenesis. The abnormal expression of spliceosome components and splicing factors, or aberrant splicing events, modulates RCD and contributes to the occurrence and progression of cancer. This review focuses on the roles of AS in tumour RCD and the underlying mechanism through which AS modulates different modes of RCD. Moreover, we summarise some potential clinical applications of targeting AS-RCD axes. This review offers systematic and mechanistic insights into tumorigenesis from the perspectives of AS and RCD, and the ultimate objective is to translate these findings into targeted therapies for cancer treatment.