YTHDF1-mediated m6A modification promotes cisplatin resistance in ovarian cancer via the FZD7/Wnt/β-catenin pathway.

Abstract

Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.