NUP62 promotes breast cancer progression and inhibits ferroptosis by stabilizing NRF2 in a KEAP1-dependent way

Identification of drug resistance drivers of breast cancer (BC) is a multifaceted challenge. Here, we demonstrated that NUP62 is significantly upregulated in BC tissues and cell lines, and its high expression correlates with a poor prognosis. Functional experiments revealed that NUP62 promotes BC cell proliferation, migration, and malignant phenotypes, while inhibiting ferroptosis. Mechanistically, NUP62 competitively binds to KEAP1, disrupting KEAP1-mediated ubiquitination and degradation of NRF2. This stabilization promotes NRF2 nuclear translocation, enhancing the transcription of antioxidant genes and inhibiting ferroptosis. Crucially, eribulin-identified through virtual screening of FDA-approved compounds-selectively inhibited NUP62, destabilizing NRF2 and abrogating its nuclear localization. In vivo, eribulin or NUP62 silencing significantly suppressed tumor growth in xenograft models. Our findings establish the NUP62-KEAP1-NRF2 axis as a master regulator of ferroptosis in BC, positioning eribulin as a promising therapeutic agent for NUP62-high tumors.