Epitranscriptomic Regulation of Platinum Resistance via the METTL3-ADAM23 Axis in Ovarian Cancer

N6-methyladenosine (m⁶A) has emerged as a pivotal regulator of post-transcriptional gene control, yet its contribution to chemotherapy resistance remains insufficiently defined. Here, we describe a previously unrecognized METTL3-ADAM23 epitranscriptomic regulatory relationship associated with platinum (Pt) resistance in ovarian cancer (OC). We show that cisplatin treatment increases global m⁶A levels and METTL3 expression, linking Pt exposure to activation of the m⁶A machinery. Functional perturbation studies demonstrate that METTL3 overexpression enhances cisplatin resistance, whereas METTL3 knockdown or pharmacologic inhibition with the selective METTL3 inhibitor STM2457 sensitizes OC cells to Pt treatment in vitro and improves Pt response in vivo. Transcriptomic profiling identifies ADAM23, a cell-adhesion-related tumor suppressor, as a METTL3-dependent, m⁶A-associated transcript, with altered mRNA expression observed across multiple experimental systems and several high-confidence predicted m⁶A sites within its transcript. Cisplatin-associated METTL3 upregulation correlates with reduced ADAM23 expression, suggesting a potential regulatory relationship that may contribute to chemoresistance. Together, these findings support a model in which METTL3-associated increases in m⁶A methylation are linked to Pt resistance, in part through modulation of ADAM23 expression, and highlight METTL3 as a potential therapeutic target in OC.