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

Sepsis is a life-threatening condition that often leads to ARDS, characterized by widespread inflammation and vascular injury. This study identifies lactate-driven lysine lactylation (Kla) as a crucial regulator of EC activation during sepsis-induced ARDS. "Our findings reveal for the first time that glycolysis-derived H3K14 lactylation (H3K14la) plays a key role in endothelial dysfunction by regulating the transcription of ferroptosis-related genes, including transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1)," said Dr. Chen, lead researcher of the study.

The study employed integrative lactylome and proteome analyses in septic mice, identifying over 980 Kla sites across 389 proteins in lung tissues. These findings highlight the significant impact of lactylation on energy metabolism, immune responses, and endothelial function. By using glycolysis inhibitors like 2-deoxy-D-glucose (2DG) and oxamate, the researchers showed that inhibition of lactate production decreased H3K14la levels, alleviated EC activation, and improved survival rates in septic mice.

The most striking finding was that H3K14la induced ferroptosis in endothelial cells, a form of iron-dependent cell death, by modulating the expression of TFRC and SLC40A1. The study demonstrated that ferroptosis inhibition using ferrostatin-1 (Fer-1) or deferoxamine (DFO) significantly reduced EC activation, mitigating sepsis-induced vascular injury and inflammation.

"Our study not only establishes the glycolysis/H3K14la/ferroptosis axis as a key pathway in sepsis-induced endothelial dysfunction but also suggests that targeting this axis could provide a novel therapeutic approach for treating sepsis-associated ARDS," added Dr. Chen.

The researchers further explored the role of histone lactylation in regulating gene transcription. They found that H3K14la primarily acts as a transcriptional activator at the promoters of iron metabolism-related genes, driving EC activation during sepsis. "These findings add a new layer of understanding to the molecular mechanisms of sepsis-related organ dysfunction, emphasizing the need to investigate lactate-induced histone modifications in future studies," said Dr. Chen.

While the study offers promising new insights into sepsis-induced endothelial dysfunction, it also highlights the need for further research. The team acknowledges that other post-translational modifications, such as acetylation and methylation, may also affect gene expression at the same histone loci. Future work will focus on exploring the crosstalk between these modifications and the role of histone deacetylases in regulating H3K14la in sepsis.

In summary, the study reveals how sepsis-induced lactate production activates endothelial cells and promotes ferroptosis through H3K14 lactylation, ultimately leading to vascular injury and lung dysfunction. These findings open up new avenues for the development of targeted therapies aimed at regulating histone modifications and ferroptosis in the treatment of sepsis-related ARDS.