Histone H3 lysine 18 lactylation promotes alveolar epithelial cell apoptosis in sepsis-induced lung injury by upregulating caspase-8 in vivo and in vitro.

BACKGROUND

Sepsis is a leading cause of acute lung injury (ALI), with apoptosis of alveolar epithelial cells (AECs) playing a central role. Elevated lactate, a hallmark of sepsis-induced metabolic reprogramming, has recently been implicated in lysine lactylation. However, its contribution to AEC apoptosis and ALI pathogenesis remains unclear.

METHODS

A cecal ligation and puncture (CLP) mouse model and LPS-stimulated AECs were used to investigate the role of lysine lactylation in AEC apoptosis. Histopathological analysis, western blotting, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, chromatin immunoprecipitation (ChIP) assays, and pharmacological interventions with Oxamate, recombinant TNF-α, and the caspase-8 inhibitor Z-IETD-FMK were performed.

RESULTS

Compared with sham controls, septic mice exhibited significantly elevated lactate levels, enhanced inflammation, increased pulmonary apoptosis, and aggravated lung injury. Both septic lung tissues and LPS-stimulated AECs showed significant upregulation of pan-lysine lactylation (pan-Kla) and histone H3 lysine 18 lactylation (H3K18la). ChIP analysis showed that H3K18la was highly enriched in the caspase-8 promoter region. Consistently, lactate exposure increased caspase-8 expression, which potentiated TNF-α-induced apoptosis in AECs. Pharmacological inhibition of lactate production or caspase-8 activity significantly alleviated pulmonary apoptosis and lung injury in septic mice.

CONCLUSION

Our results demonstrate that lactate-driven H3K18la promotes TNF-α-induced AEC apoptosis by upregulating caspase-8 in sepsis-induced ALI. Targeting this lactate/H3K18la/caspase-8 axis may represent a promising therapeutic strategy for sepsis-induced ALI.