m6A writer WTAP targets NRF2 to accelerate bladder cancer malignancy via m6A-dependent ferroptosis regulation.

Recent evidence have indicated that ferroptosis, a novel iron-dependent form of non-apoptotic cell death, plays a critical role in human cancers. Besides, emerging literatures have revealed the ovel function of N-methyladenosine (mA) in bladder cancer physiological. However, the underlying mechanism of mA on bladder cancer is still unclear. Here, present work revealed that mA methyltransferase ('writer') WTAP up-regulated in bladder cancer tissue and cells, indicating the poor prognosis of bladder cancer patients. Functionally, gain/loss-of-functional experiments illustrated that WTAP promoted the viability of bladder cancer cells and inhibited the erastin-induced ferroptosis. Mechanistically, there was a remarkable mA modification site on 3'-UTR of endogenous antioxidant factor NRF2 RNA and WTAP could install its methylation. Moreover, mA reader YTHDF1 recognized the mA site on NRF2 mRNA and enhanced its mRNA stability. Therefore, these findings demonstrated potential therapeutic strategyies for bladder cancer via mA-dependent manner.