Hypoxia‐Induced Histone Lactylation Promotes Ferroptosis in Cardiomyocytes via the Wnt/β‐Catenin Pathway

This study investigated the effects of histone lactylation on ferroptosis in hypoxia-induced cardiomyocytes. A hypoxia model was established in AC16 cells treated with 2-Deoxy-D-glucose (2-DG, a glucose analogue), ferrostatin-1 (Fer-1, a selective ferroptosis inhibitor), lactate (LA), sh-β-catenin (shRNA of β-catenin), or SKL2001 (an agonist of the Wnt/β-catenin pathway) for subsequent experiments. Hypoxia increased glycolysis ability, HK2, PDK1, and LDHA mRNA expression, HK and LDH activities, and LA levels in AC16 cells, decreased SLC7A11 and GPX4 protein levels and GSH levels, and elevated iron ion, MDA, and ROS levels, Wnt3 and nuclear β-catenin protein levels, β-catenin nucleus entry, the overall level of lactylation, the lactylation of β-catenin, and β-catenin protein stability. 2-DG or Fer-1 treatment reduced iron ion, MDA, and ROS levels but increased SLC7A11 and GPX4 protein levels and GSH levels in hypoxia-treated cells. 2-DG treatment decreased Wnt3 and nuclear β-catenin protein levels, β-catenin nucleus entry, the overall level of lactylation, the lactylation of β-catenin, and β-catenin protein stability, whereas LA treatment produced the opposite effects. Wnt/β-catenin pathway repression attenuated hypoxia-induced ferroptosis in cardiomyocytes. Collectively, hypoxia enhances histone lactylation, activates the Wnt/β-catenin pathway, and increases β-catenin stability, thereby promoting ferroptosis in cardiomyocytes.