LDHB K156 lactylation links cGAS-STING-mediated metabolic reprogramming to NLRP3 inflammasome activation in sepsis-associated acute kidney injury.

AIMS: Sepsis-associated acute kidney injury (SA-AKI) pathogenesis remains incompletely understood. This study aimed to elucidate the immunometabolic mechanisms driving SA-AKI, focusing on the role of metabolic reprogramming and non-histone protein lactylation in amplifying renal inflammation.

MATERIALS AND METHODS: We utilized a cecal ligation and puncture (CLP) mouse model and lipopolysaccharide (LPS)-stimulated HK-2 cells. Evaluations included lactyl-proteomic screening, cellular metabolic/biochemical assays, and in vivo adeno-associated virus (AAV)-mediated renal tubule-specific expression of wild-type (WT) or lactylation-deficient mutant (K156R) lactate dehydrogenase B (LDHB).

KEY FINDINGS: Sepsis induced pronounced glycolysis, lactate accumulation, and NLRP3 inflammasome activation. Lactyl-proteomics revealed significant upregulation of LDHB lysine 156 (K156) lactylation. Mechanistically, upstream cGAS-STING signaling promoted glycolytic reprogramming and lactate production, providing substrates for LDHB K156 lactylation, which was regulated by the EP300/HDAC2 axis. In vivo, compared with the K156R mutant, LDHB WT exacerbated renal dysfunction, histopathological injury, and inflammasome activation.

SIGNIFICANCE: LDHB K156 lactylation represents a critical molecular nexus linking cGAS-STING-mediated metabolic dysregulation to inflammatory amplification. Targeting this lactylation regulatory axis offers a potential mechanism-oriented therapeutic strategy for SA-AKI.