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p62 is associated with 2 major cellular defense mechanisms against metabolic and oxidative stress, autophagy and the Kelch‐like ECH‐associated protein 1 (KEAP1)‐nuclear factor‐E2‐related factor 2 (NRF2) system. Recent studies indicate that the p62‐KEAP1‐NRF2 pathway promotes tumorigenesis and tumor growth mediated by NRF2‐dependent antioxidative response. However, whether p62 is involved in bladder cancer (BCa) development remains unknown. Here, we found that p62 is overexpressed in BCa tissue and several BCa cell lines. The knockdown of p62 inhibits BCa cell growth both in vitro and in vivo, with increased intracellular reactive oxygen species level. Mechanically, p62 activates NRF2 signaling by sequestrating KEAP1, which leads to the upregulation of antioxidant genes ( Gclc ,  Gstm5 , and  Gpx2 ), thus protecting BCa cells from oxidative stress. Our findings indicate that p62 might be involved in the development of BCa and serve as a potential therapeutic target.

p62 promotes bladder cancer cell growth by activating KEAP1/NRF2‐dependent antioxidative response