Disruption of the SNRPF–DDX24–E2F4 Feedback Loop Uncouples Splicing and Transcriptional Regulation to Suppress Ovarian Cancer Progression

ABSTRACT Ovarian cancer (OC) remains a major cause of gynecologic cancer mortality, with progress in targeted therapy limited by an incomplete understanding of post‐transcriptional oncogenic drivers. Dysregulated RNA splicing—particularly intron retention (IR)—is increasingly recognized as a key driver of tumor progression. Here, integrated transcriptomic and proteomic analyses identify SNRPF, a core spliceosomal component, as a potent oncogenic driver in OC. SNRPF is highly expressed in tumor specimens, and its overexpression predicts poor patient survival. Silencing SNRPF suppresses proliferation, invasion, and xenograft growth. IR‐focused analysis reveals that SNRPF depletion induces intron 6 retention in DDX24, disrupting the Helicase_C domain and generating premature termination codons that activate nonsense‐mediated decay (NMD), thereby reducing DDX24 protein abundance and markedly impairing its oncogenic function. DDX24 depletion similarly promotes intron 2 retention in E2F4, causing NMD‐mediated downregulation. Notably, E2F4 directly binds the SNRPF promoter, forming a self‐sustaining “SNRPF–DDX24–E2F4” axis linking splicing and transcriptional regulation. Antisense oligonucleotide‐mediated inhibition of SNRPF disrupts this feedback loop, downregulates DDX24 and E2F4 via IR, and significantly impairs tumor growth in vitro, in vivo, and in patient‐derived xenografts. These findings define a splicing–transcription coupling mechanism in OC and position SNRPF as a promising therapeutic target.