<p>Sunitinib, a first-line tyrosine kinase inhibitor, is widely used for renal cell carcinoma (RCC) therapy; however, sunitinib resistance compromises clinical efficacy. N6-methyladenosine (m⁶A), the most prevalent internal RNA modification, plays a crucial role in cancer progression and drug response. This study aimed to investigate the regulatory mechanism of an m⁶A writer ZC3H13 on secreted frizzled-related protein 4 (sFRP-4) and reveal their roles in sunitinib resistance of RCC. The levels of sFRP-4 and ZC3H13 were evaluated by qRT-PCR and western blotting. Cell functional assays and in vivo experiments, were conducted to explore the effects of sFRP-4 and ZC3H13 on sunitinib resistance of RCC. The regulatory relationship between ZC3H13 and sFRP-4 was confirmed via qRT-PCR, western blotting, luciferase, MeRIP and RNA stability assays. Wnt/β-catenin pathway was examined by western blotting. sFRP-4 was downregulated in sunitinib-resistant RCC tissues and cells. Forced expression of sFRP-4 suppressed sunitinib-resistant RCC cell viability, migration, invasion, and tumor growth under sunitinib exposure by attenuating Wnt/β-catenin pathway. Mechanistically, ZC3H13 enhanced sFRP-4 mRNA stability by increasing its m⁶A modification. Knockdown of ZC3H13 could reverse the inhibitory effects of sFRP-4 on sunitinib resistance of RCC cells. In summary, ZC3H13-mediated m⁶A modification stabilizes sFRP-4 expression, which suppresses Wnt/β-catenin signaling and attenuates the sunitinib resistance of RCC. The ZC3H13/sFRP-4 axis may represent a promising therapeutic target in RCC.</p>