H3K18la Facilitates TRA2A-Mediated Alternative Splicing of STIL, Suppressing Ferroptosis and Cisplatin Treatment Sensitivity in Ovarian Cancer.

Purpose: Ovarian cancer (OC) is a common and highly lethal malignant tumor in women. Due to its hidden early symptoms, most patients are diagnosed at an advanced stage, and the tumor often develops resistance to chemotherapy, making treatment challenging. Elucidating the mechanisms of OC development and identifying new therapeutic targets, are crucial for improving treatment outcomes.

Materials and methods: We used bioinformatics analysis combined with qRT-PCR, WB, and IHC to study TRA2A expression and histone lactylation in OC samples. CCK8, clone formation, EdU, and Transwell experiments were used to assess OC cells proliferation. RT-PCR analyzed TRA2A-mediated alternative splicing. And the nude mouse xenograft model was constructed to validate TRA2A's molecular function in vivo.

Results: This study reveals a novel mechanism by which OC cells evade ferroptosis through the TRA2A-STIL signaling axis. Specifically, H3K18la is significantly enriched at the promoter region of the TRA2A gene, activating its transcription and upregulating expression. The upregulated TRA2A protein, functioning as a key splicing factor, specifically regulates alternative splicing (AS) of the STIL mRNA. This promotes expression of the STIL-L isoform, which inhibits ferroptosis in OC cells by modulating iron metabolism. Furthermore, targeted knockdown of TRA2A combined with cisplatin treatment significantly enhanced the therapeutic efficacy against OC. Consequently, targeting TRA2A-mediated AS represents a promising novel therapeutic target for OC.

Conclusion: This study uncovers for the first time a novel mechanism by which OC cells evade ferroptosis via an H3K18la-modified TRA2A-STIL signaling axis, thereby establishing a promising new therapeutic target for OC treatment.