RNA splicing dysregulation in hepatocellular carcinoma: Molecular mechanisms, therapeutic targets, and intervention strategies—A comprehensive review

Alternative splicing (AS) is a fundamental biological process that expands genomic diversity and finely regulates cellular functions through the generation of multiple mRNA isoforms from a single gene. Its dysregulation has been strongly implicated in the pathogenesis of hepatocellular carcinoma (HCC). This review expounds on the pivotal role of aberrant AS events in driving HCC initiation and progression, highlighting how etiological factors, including metabolic dysfunction-associated steatotic liver disease (MASLD) and viral hepatitis, disrupt normal splicing mechanisms, thereby promoting carcinogenesis. Although AS contributes significantly to key malignant features of HCC, such as metabolic reprogramming, enhanced invasion, metastasis, and drug resistance, a systematic understanding of these mechanisms remains incomplete. In this review, we comprehensively explore the regulatory networks mediated by AS in HCC, identify promising therapeutic targets, and elucidate their functional crosstalk during multistep hepatocarcinogenesis. Furthermore, recent advances in pharmacological strategies are summarized, including small-molecule inhibitors and antisense oligonucleotides (ASOs) that target AS, followed by a discussion of persistent challenges along with future research directions. By synthesizing current evidence, this review establishes a robust theoretical foundation and provides innovative perspectives for the development of AS-based precision therapeutics against HCC.