NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.

ABSTRACT: Lactate-mediated lactylation on target proteins is recently identified as the novel posttranslational modification with profound biological functions. RNA 5-methylcytosine (m⁵C) modification possesses dynamic and reversible nature, suggesting that activity of its methyltransferase NSUN2 is actively regulated. However, how NSUN2 activity is response to acidic condition in tumor microenvironment and then regulates cancer cell survival remain to be clarified. Here, we demonstrate that NSUN2 activity is enhanced by lactate-mediated lactylation at lysine 508, which then targets glutamate-cysteine ligase catalytic subunit (GCLC) mRNA to facilitates GCLC m⁵C formation and mRNA stabilization. The activated GCLC induces higher level of intracellular GSH accompanied by decrease

SUBMITTER: Niu K 

PROVIDER: S-EPMC11750563 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature