Background <p>Pancreatic cancer (PC) is characterized by high chemoresistance and poor prognosis. CUL2, a scaffold protein of E3 ubiquitin ligases, has been implicated in tumor progression, but its role in PC remains unclear.</p> Methods <p>CUL2 expression was analyzed in PC tissues and cell lines using TCGA and GEO datasets, qRT-PCR, Western blot, and immunohistochemistry analysis. The biological functions of CUL2 were investigated through gain- and loss-of-function studies in vitro. The impact of CUL2 overexpression on gemcitabine sensitivity was evaluated in xenograft models. Molecular mechanisms were explored using proteasome inhibitor MG132, co-immunoprecipitation, subcellular fractionation, and ferroptosis assessment.</p> Results <p>CUL2 was significantly upregulated in PC tissues and correlated with poor prognosis. CUL2 promoted PC cell proliferation, migration, and EMT. Mechanistically, CUL2 competed with NRF2 for KEAP1 binding, thereby preventing KEAP1-mediated NRF2 degradation and promoting NRF2 nuclear translocation. CUL2 promoted oxidative stress while activating NRF2-dependent antioxidant response. The CUL2-NRF2 axis suppressed ferroptosis and conferred gemcitabine resistance in PC cells. In xenograft models, CUL2 overexpression enhanced tumor growth and attenuated gemcitabine sensitivity through NRF2-mediated ferroptosis inhibition.</p> Conclusions <p>Our findings reveal a novel mechanism whereby CUL2 promotes PC progression and ferroptosis resistance through regulation of the KEAP1-NRF2 axis. CUL2 overexpression enhances cellular antioxidant capacity and maintains mitochondrial integrity, thereby conferring broad resistance to ferroptosis-inducing conditions. This study suggests that targeting the CUL2-NRF2 axis to enhance ferroptosis sensitivity might represent a promising therapeutic strategy for PC treatment.</p> Graphical abstract <p></p>