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

Summary

Using lactylome/proteome profiling and Cut&Tag in septic mice, the authors show that lactate-driven H3K14 histone lactylation in pulmonary endothelial cells enriches at ferroptosis gene promoters (TFRC, SLC40A1), linking hyperglycolysis to endothelial ferroptosis and lung injury. Inhibiting glycolysis reduced H3K14la and EC activation, nominating the glycolysis–H3K14la–ferroptosis axis as a therapeutic target in sepsis-associated ARDS.

Key Findings

• Septic mice exhibited elevated lung lactate and H3K14 lactylation, particularly in pulmonary endothelial cells.
• Glycolysis suppression reduced H3K14la levels and endothelial activation, linking metabolic flux to epigenetic regulation.
• H3K14la was enriched at promoters of ferroptosis-related genes (TFRC, SLC40A1), promoting endothelial activation and lung injury.
• Identifies a glycolysis–H3K14la–ferroptosis axis as a mechanistic driver of vascular dysfunction in sepsis-associated ARDS.

Clinical Implications

Targeting glycolysis, histone lactylation, or ferroptosis in the pulmonary endothelium may mitigate vascular leak and organ injury in sepsis-associated ARDS, motivating translational studies of glycolysis inhibitors or ferroptosis modulators.

Limitations

• Findings are primarily in murine models without human tissue validation.
• Causal manipulation of specific ferroptosis targets downstream of H3K14la in vivo requires further confirmation.

Future Directions

Validate H3K14la–ferroptosis signatures in human ARDS endothelium, test pharmacologic modulators (glycolysis inhibitors, ferroptosis blockers), and dissect cell-type specificity and timing in sepsis models.