PDK4-Mediated VDAC2 Lactylation Links Glycolysis to Autophagy Failure in Septic Cardiomyopathy

Background: Elevated lactate is a critical prognostic biomarker in sepsis, strongly associated with increased mortality. Sepsis-induced cardiomyopathy (SICM) is a major contributor to poor outcomes in septic patients, yet the mechanisms linking lactate elevation to SICM pathogenesis remain incompletely understood. Methods: We combined experimental murine models of sepsis with patient cohort analyses to investigate the metabolic and molecular mechanisms underlying SICM. Glycolytic flux, lactate production, and protein lactylation were assessed using metabolomics, proteomics, and site-directed mutagenesis. The clinical relevance of pyruvate dehydrogenase kinase 4 (PDK4) was evaluated by correlating serum levels with lactate and cardiac injury biomarkers in septic patients. Results: In experimental SICM, PDK4 upregulation enhanced glycolysis and promoted lactate accumulation. Elevated lactate induced lactylation of voltage-dependent anion channel 2 (VDAC2), specifically at lysine 75 (K75). Mechanistically, VDAC2 K75 lactylation disrupted its interaction with neighbor of BRCA1 gene 1 (NBR1), suppressing cardiomyocyte autophagy and exacerbating myocardial injury. Clinically, serum PDK4 levels positively correlated with lactate and cardiac injury markers, showing strong predictive value for SICM (AUC = 0.8516). Conclusions: Our findings identify a pathogenic axis whereby PDK4-driven metabolic reprogramming promotes VDAC2 lactylation, impairs cardiomyocyte autophagy, and accelerates cardiac dysfunction in SICM. Targeting the PDK4?lactate?VDAC2 pathway may represent a novel therapeutic strategy for improving outcomes in septic cardiomyopathy.