HPD is an m6A Methyltransferase that Protects Colorectal Cancer Cells from Ferroptotic Cell Death by m6A Methylating SLC7A11/GPX4

This study reveals that the tyrosine metabolic enzyme HPD functions as a previously uncharacterized, METTL3‐independent m6A methyltransferase. It promotes colorectal tumor progression by coordinately regulating the SLC7A11/GPX4 axis to suppress ferroptosis. This finding expands the family of m6A writers and reveals a promising new target for therapeutic intervention. Abstract N6‐methyladenosine (m6A) 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 m6A 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 m6A‐mediated ferroptosis and underscore the potential to target the m6A methyltransferase activity of HPD for cancer treatment. This study reveals that the tyrosine metabolic enzyme HPD functions as a previously uncharacterized, METTL3-independent m 6 A methyltransferase. It promotes colorectal tumor progression by coordinately regulating the SLC7A11/GPX4 axis to suppress ferroptosis. This finding expands the family of m 6 A writers and reveals a promising new target for therapeutic intervention. 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. Advanced Science, EarlyView.