The current molecular basis by which the signaling pathway is activated to protect against ferroptosis is still ambiguous in melanoma. Therefore, we focused to identify suspicious genes. Here, with TCGA melanoma data, we utilized weighted gene co-expression analysis combined with a molecular subtype clustering model to prioritize potential novel oncogenes and validated them in vitro and in vivo. We found that the expression of centrosomal protein 290 (CEP290) is increased in melanoma tissues and cells compared to normal controls and that its repression promotes iron and malondialdehyde (MDA) accumulation. Mechanistically, CEP290 binds Nrf2 to displace Keap1, thus inhibiting Nrf2 ubiquitination, stabilizing the Nrf2 protein and activating Nrf2 signal transduction. Interestingly, the expression of CEP290 is also regulated by the recruitment of Nrf2 to its promoter. The direct interplay between CEP290 and Nrf2 forms a positive feedback loop. Moreover, inhibition of Nrf2 significantly enhances the ferroptotic effects of CEP290 knockout in vivo. These results shed more light on the important role of CEP290 in connecting ferroptosis and reveal a novel mechanism by which CEP290 hyperactivation accelerates melanoma progression and protects against ferroptosis via aberrant Nrf2 signaling, presenting an important implication for melanoma treatment.