METTL3 promotes ovarian cancer progression through YTHDF2-dependent degradation of GATA4.

Ovarian cancer (OC) remains a highly lethal gynecological malignancy with limited therapeutic options due to its aggressive progression and therapeutic resistance. N6-methyladenosine (m6A) RNA modification has emerged as a critical regulator of tumorigenesis, but the specific mechanisms linking m6A regulators to OC progression require further clarification. Here, we report that METTL3 promotes OC progression by enhancing YTHDF2-dependent degradation of the tumor suppressor GATA4. Mechanistically, METTL3-mediated hypermethylation of GATA4 transcripts at nucleotides 1837 and 2432 promotes YTHDF2-dependent mRNA decay, thereby suppressing GATA4 expression. Pharmacological inhibition of METTL3 with STM2457 increases GATA4 abundance, and attenuates malignant phenotypes of OC. Single-cell RNA sequencing (scRNA-seq) revealed that GATA4 was markedly downregulated in granulosa cells, fibroblasts, and endothelial cells within the OC microenvironment, potentially linking its loss to aberrant epithelial-mesenchymal transition (EMT), abnormal proliferation, and stromal remodeling. In conclusion, our findings establish a METTL3-YTHDF2 regulatory axis that destabilizes GATA4 mRNA, providing novel insights into the epigenetic control of OC progression. Thus, targeting this axis may offer promising therapeutic strategies to improve outcomes for OC patients.