Histone lactylation exacerbates acute lung injury in septic mice by promoting ferroptosis in pulmonary microvascular endothelial cells.

Summary

In a septic mouse model and primary endothelial cells, elevated lactate drove H3K18 histone lactylation, upregulating ACSL4 and ferritinophagy (via GATA2→LC3/NCOA4), which induced endothelial ferroptosis and increased vascular permeability, worsening acute lung injury. Human S-ARDS data linked serum lactate and ferroptosis markers to poor prognosis, highlighting actionable epigenetic-ferroptotic targets.

Key Findings

• Serum lactate peaked 18 h after CLP and promoted endothelial ferroptosis, increasing pulmonary vascular permeability and aggravating ALI.
• Lactate increased H3K18 histone lactylation, driving ACSL4 transcription and lipid peroxidation in MPMVECs.
• H3K18la also enhanced LC3 transcription and, via GATA2, upregulated NCOA4 to facilitate ferritinophagy.
• In S-ARDS patients, serum lactate correlated with ferroptosis levels and poor prognosis.

Clinical Implications

Targets such as ACSL4, histone lactylation, and ferritinophagy could be leveraged with ferroptosis inhibitors or epigenetic modulators; lactate control may mitigate endothelial injury in sepsis-associated ARDS.

Limitations

• Preclinical model; translational relevance requires validation in human tissues and interventional studies
• Human data are correlational; sample sizes and reproducibility across centers not reported

Future Directions

Test ferroptosis inhibitors or epigenetic modulators targeting H3K18la/ACSL4/ferritinophagy in sepsis-ALI models, and validate biomarkers in prospective S-ARDS cohorts.