H3K14la drives endothelial dysfunction in sepsis-induced ARDS by promoting SLC40A1/transferrin-mediated ferroptosis.

Summary

In septic mice, lactate-driven H3K14 lactylation increases in pulmonary ECs, promoting ferroptosis via transcriptional upregulation at TFRC and SLC40A1 promoters. Inhibiting glycolysis reduced H3K14la and EC activation, highlighting a glycolysis–lactylation–ferroptosis axis as a therapeutic target in sepsis-associated ARDS.

Key Findings

• Septic mouse lungs exhibited elevated lactate and H3K14 lactylation, especially in pulmonary endothelial cells.
• Glycolysis inhibition decreased H3K14la and endothelial activation, linking metabolism to epigenetic regulation.
• H3K14la was enriched at TFRC and SLC40A1 promoters, promoting ferroptosis and vascular dysfunction in sepsis-induced lung injury.

Clinical Implications

Identifies potential targets (glycolysis, H3K14 lactylation, ferroptosis effectors) for pharmacologic modulation in septic ARDS; supports exploring ferroptosis inhibitors or lactylation modulators.

Limitations

• Preclinical mouse model without human validation limits direct clinical generalizability
• Therapeutic modulation of H3K14la/ferroptosis was not tested in interventional in vivo studies

Future Directions

Validate H3K14la targets in human septic ARDS tissues; evaluate pharmacologic inhibitors of lactylation/ferroptosis in relevant models and early-phase trials.