EZH2 lactylation: a key epigenetic regulator and potential therapeutic target for sepsis-associated lung injury

Sepsis-associated lung injury (SALI) is a lethal infection-induced complication with high mortality and limited targeted therapies. Dysregulated lactate metabolism is closely linked to SALI, yet the underlying mechanisms remain unclear.

This study aims to investigate the role and molecular mechanism of EZH2 (Enhancer of zeste homolog 2) lactylation in SALI development, thereby uncovering a novel exploitable therapeutic target.

A total of 209 ICU patients were enrolled and divided into the SALI group (n = 104) and non-SALI group (n = 105) to detect serum lactate levels. Cecal ligation and puncture (CLP) mouse models and endothelial cell-specific Ezh2 knockout (Ezh2^ECKO) mouse models were established. Combined with lactate and lactate dehydrogenase inhibitor intervention, multi-omics analysis, ChIP, qPCR, immunofluorescence and other techniques were used in the study.

Serum lactate levels were significantly elevated in patients with SALI and model mice, and lung tissue lactate levels were elevated in model mice. Lactate levels were positively associated with inflammatory markers and lung injury severity. EZH2 underwent site-specific lactylation at lysine 30 and 406 (EZH2 K30/K406la) in SALI, which was enhanced with disease progression. Inhibiting lactate production or EZH2 lactylation improved pulmonary function, reduced inflammatory infiltration and pathological lung tissue damage. EZH2 K30/K406la downregulated CITED2 (CBP-p300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2) expression by reducing its occupancy at the CITED2 promoter and altering CITED2 promoter activity, relieving the inhibition of the NF-κB (Nuclear Factor-kappa B) pathway and exacerbating inflammatory responses and endothelial dysfunction.

EZH2 lactylation aggravates SALI via the CITED2/NF-κB axis, highlighting this epigenetic modification as a promising therapeutic target that opens a new pharmacological avenue for developing site-specific inhibitors to combat SALI.