Kat2a-Mediated Histone Lactylation Promotes Ferroptosis and Inflammation in Sepsis-Associated Lung Injury

The mortality rate of sepsis-associated acute lung injury (ALI) remains high, with its core mechanisms closely linked to macrophage-mediated inflammation and ferroptosis. Lipopolysaccharide (LPS), a key factor in Gram-negative bacterial infections, can activate epigenetic modifications and induce ferroptosis. However, the role of Kat2a-mediated histone lactylation (H3K18la) in ALI and its interaction with ferroptosis remain unclear. This study aims to investigate the pathogenic mechanism of the Kat2a-H3K18la axis in ALI through its regulation of the cholesterol metabolism enzyme CH25H and the ferroptosis pathway, as well as to evaluate targeted intervention strategies. Our study revealed LPS significantly upregulated Kat2a expression and H3K18la modification levels in lung tissues and macrophages. Inhibition of the Kat2a-H3K18la axis by MB-3 alleviated pulmonary hemorrhage, edema, fibrosis, and inflammatory infiltration while reducing NLRP3 inflammasome activation and M1 macrophage polarization. Kat2a-H3K18la epigenetically regulated ferroptosis bidirectionally, promoting transferrin receptor (Tfrc) transcription while suppressing protective genes Slc7a11/GPX4. Finally, we revealed that the exogenous lactate specifically reversed MB-3 inhibitory effect on ferroptosis, uncovering a novel "lactate metabolism-H3K18la modification-ferroptosis" pathway. In summary, our research reveals a new function for the Kat2a-ferroptosis axis in acute lung injury, revealing important information for possible therapeutic approaches.