Qihua Peng, Kaho Leung, Yixuan Sun, Shiyu Zhang, Yincheng Teng, Xiaojuan Dong
BACKGROUND: Cisplatin resistance remains a major obstacle in the treatment of ovarian cancer (OC). Although ELK3, an ETS transcription factor, has been implicated in chemoresistance across various cancers, its specific role and molecular mechanisms in OC progression and cisplatin resistance remain poorly understood. METHODS: ELK3 expression was analyzed in cisplatin-resistant OC cells using qPCR and Western blotting. Functional assays, including CCK-8, apoptosis analysis, and xenograft models, were employed to assess the impact of ELK3. Mechanistic insights were gained through Co-IP and histone lactylation analysis. RESULTS: ELK3 was significantly upregulated in cisplatin-resistant OC tissues and cells, and its elevated expression correlated with poor patient survival according to TCGA and KM Plotter data. Knockdown of ELK3 sensitized OC cells to cisplatin by suppressing CHD4 expression and reducing histone lactylation levels. Importantly, restoration of CHD4 expression rescued cisplatin resistance in ELK3-deficient cells. CONCLUSION: The ELK3-CHD4-histone lactylation axis plays a critical role in driving cisplatin resistance in OC, highlighting its potential as a novel therapeutic target for overcoming chemoresistance.