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

C formation and mRNA stabilization. The activated GCLC induces higher level of intracellular GSH accompanied by decreased lipid peroxidation and resistant phenotype to ferroptosis induction by doxorubicin (Dox) in gastric cancer cells. Specifically, the effect of NSUN2 lactylation-GCLC-GSH pathway is nearly lost when NSUN2 K508R or GCLC C-A mutant (five cytosine sites) was introduced into the cancer cells. We further identify the catalytic subunit N-α-acetyltransferase 10 (NAA10) as the lactytransferase of NSUN2, and lactate treatment substantially enhances their association and consequent NSUN2 activation. Taken together, our findings convincingly elucidate the signaling axis of NAA10-NSUN2-GCLC that potently antagonizes the ferroptosis under acidic condition, and therefore, targeting NSUN2 lactylation might be an effective strategy in improving the prognosis of cancer patients.