Jiyan Wang, Xintong Dai, Huanle Liu, Saiwei Hua, Hongkai Chang, Huanran Sun, Mingming Sun, Huifang Zhao, Kemin Ni, Fei Xie, Yaya Qiao, Qingle Gao, Chenxi Yu, Qijun Zhang, Jianshuang Guo, Chunze Zhang, Shuai Zhang, Changliang Shan
Abstract N6‐methyladenosine (m 6 A) is a dynamic RNA modification, which is added by the METTL3‐METTL14 methyltransferase complex or METTL16. Unexpectedly, the tyrosine metabolism enzyme 4‐hydroxyphenylpyruvate dioxygenase (HPD) is discovered as a methyltransferase responsible for m 6 A modification. Unlike METTL3, which requires the assistance of METTL14 to form a complex and exert methyltransferase activity. Interestingly, it is revealed that HPD has a catalytic domain (CMI) like METTL3. Moreover, HPD recruits the universal cofactor S‐adenosylmethionine (SAM) to the substrate binding center as a methyl group donor. In particular, it is demonstrated that HPD regulates colorectal cancer ferroptosis by methylating SLC7A11/GPX4 through a moonlighting function. These findings uncover the moonlighting function of HPD in m 6 A‐mediated ferroptosis and underscore the potential to target the m 6 A methyltransferase activity of HPD for cancer treatment.