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

BackgroundElevated 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. MethodsWe 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. ResultsIn 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). ConclusionsOur 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. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIElevated lactate is strongly associated with mortality in sepsis, but its mechanistic contribution to SICM was unknown. C_LIO_LIThis study identifies a pathogenic axis in which PDK4 promotes glycolysis-dependent lactate accumulation, driving VDAC2 lactylation at lysine 75. C_LIO_LIVDAC2 lactylation disrupts interaction with NBR1, impairs autophagy, and exacerbates cardiac injury. C_LIO_LIIn septic patients, serum PDK4 levels correlate with lactate and cardiac injury markers, showing predictive value for SICM. C_LI What Are the Clinical Implications?O_LISerum PDK4 may serve as a potential biomarker for the identification of patients with sepsis-induced cardiomyopathy. C_LIO_LITargeting the PDK4-lactate-VDAC2 pathway represents a promising therapeutic strategy to restore autophagy and attenuate SICM. C_LIO_LIThese findings link metabolic reprogramming to SICM pathogenesis and provide a translational framework for intervention. C_LI