HPD is an m(6)A Methyltransferase that Protects Colorectal Cancer Cells from Ferroptotic Cell Death by m(6)A Methylating SLC7A11/GPX4.

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.