hnRNPA1-SF3B3 interaction drives radioresistance in oral squamous cell carcinoma by modulating MARF1 alternative splicing isoforms

Abstract Background Radioresistance remains a major obstacle in oral squamous cell carcinoma (OSCC) therapy. This study aimed to elucidate the role of abnormal alternative splicing (AS) and key splicing factors in this process, focusing on their mechanistic contributions to DNA repair. Methods We integrated RNA-sequencing data from irradiated OSCC mouse models with public datasets to profile splicing factor dynamics. Clinical relevance of hnRNPA1 was validated in an OSCC cohort. Functional roles were assessed via clonogenic survival, CCK-8, and xenograft assays. Mechanisms were delineated using co-immunoprecipitation, immunofluorescence, and analysis of MARF1 splicing and downstream DNA repair pathways. Results hnRNPA1 was significantly upregulated in OSCC tissues and correlated with poor radiotherapy response. Its knockdown suppressed OSCC cell proliferation and impaired DNA double-strand break repair. Mechanistically, hnRNPA1 interacted with SF3B3 to inhibit exon 8 skipping of MARF1, promoting the oncogenic MARF1-L isoform. MARF1-L enhanced radioresistance by degrading PPP1R10, a negative regulator of Chk1, thereby activating homologous recombination repair (HR). Conclusions These findings identified hnRNPA1 as a pivotal orchestrator of OSCC radioresistance, which, through an SF3B3-dependent MARF1 splicing switch and subsequent PPP1R10 degradation, activates HR repair. Targeting the hnRNPA1-SF3B3-MARF1 axis presents a novel therapeutic strategy to overcome radioresistance in OSCC.