BACKGROUND: It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance. METHODS: Ubiquitin-specific protease mRNA expression, was detected through RT-qPCR. In vitro functional assays assessed the effects of USP2 overexpression on DDP resistance, cell proliferation capability, and ferroptosis markers in A549/DDP and H1299/DDP cells. Ubiquitination assays evaluated the ubiquitination levels of p53 following USP2 overexpression. Co-immunoprecipitation (Co-IP) assays confirmed the binding relationship between USP2 and p53. In vivo experiments in mice explored the specific role of the USP2-p53 axis in a xenograft tumor model. RESULTS: USP2 expression was suppressed in cisplatin-resistant NSCLC cells. USP2 overexpression inhibited cell viability in cisplatin-resistant cells. Among the ferroptosis markers, the results showed that USP2 overexpression promoted LDH release, Fe CONCLUSION: USP2 acted on the K305R site of p53, which resulted in its deubiquitination. This cellular process could modulate cisplatin resistance through ferroptosis in NSCLC. This study could provide a potential therapeutic target to NSCLC.