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.

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.

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).

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. What Is New? Elevated lactate is strongly associated with mortality in sepsis, but its mechanistic contribution to SICM was unknown. This study identifies a pathogenic axis in which PDK4 promotes glycolysis-dependent lactate accumulation, driving VDAC2 lactylation at lysine 75. VDAC2 lactylation disrupts interaction with NBR1, impairs autophagy, and exacerbates cardiac injury. In septic patients, serum PDK4 levels correlate with lactate and cardiac injury markers, showing predictive value for SICM. What Are the Clinical Implications? Serum PDK4 may serve as a potential biomarker for the identification of patients with sepsis-induced cardiomyopathy. Targeting the PDK4–lactate–VDAC2 pathway represents a promising therapeutic strategy to restore autophagy and attenuate SICM. These findings link metabolic reprogramming to SICM pathogenesis and provide a translational framework for intervention. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was supported in part by grants from the National Natural Science Foundation of China (82372157 and 82072224 to Cai Li); sub-project of National Key Research and Development Program of China (2023YFC2506902 to Cai Li). The funders played no role in the design, conduct, or reporting of this study. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Ethic Committee of Nanfang Hospital (Ethics approval number: NFEC-2025-382) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Author Information Nuo Xu, Bachelor, 1775215821{at}qq.com Gan Lu, Bachelor, ganlusmu{at}163.com Jinzi Chen, Bachelor, 130496305{at}qq.com Shuangjiao Cao, PhD, caosjiao1994{at}163.com Yuhan Feng, Bachelor, fyhan0518{at}163.com Liping Huang, Master, 1154922011{at}qq.com Shirong Chen, Bachelor, 1275038963{at}qq.com Zehong Huang, Master, 1145209477{at}qq.com Jiawei NI, Bachelor, 1942283640{at}qq.com Junli Luo, Master, 376130571{at}qq.com Jiayi Wu, Bachelor, wujiayi010831{at}163.com Yili wang, Bachelor, wangyili0911{at}163.com Peiixn liu, Bachelor, liu_peixin{at}foxmail.com Kexuan Liu, MD, PhD, liukexuan705{at}163.com Cai Li, MD, PhD, licaisysu{at}163.com Data Availability All data generated or analyzed during this study are included in this article Abbreviations - PDK4 - Pyruvate Dehydrogenase Kinase 4 - VDAC2 - Voltage-Dependent Anion Channel 2 - NBR1 - Neighbor of BRCA1 Gene 1 - SICM - Sepsis-Induced Cardiomyopathy - LPS - Lipopolysaccharide - HIF-1α - Hypoxia-Inducible Factor 1-alpha - PKM2 - Pyruvate Kinase M2 Isoform - HK2 - Hexokinase 2 - PDC - Pyruvate Dehydrogenase Complex - LDHA - Lactate Dehydrogenase A - PFKFB3 - 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 - DCA - Dichloroacetate - AAV - Adeno-Associated Virus - LVEF - Left Ventricular Ejection Fraction - LVFS - Left Ventricular Fractional Shortening - cTNT - Cardiac Troponin T - CK-MB - Creatine Kinase-MB Isoform - ECAR - Extracellular Acidification Rate - SINCM - Sepsis-Induced Noncompaction Cardiomyopathy - hs-TNT - High-Sensitivity Troponin T - BNP - B-Type Natriuretic Peptide - ROC - Receiver Operating Characteristic - AUC - Area Under the Curve - VDAC2 - K75la VDAC2 Lysine 75 Lactylation - Mut - Mutant - CQ - Chloroquine - CBP - CREB-Binding Protein - CO-IP - Co-Immunoprecipitation - iCBP - Inhibitor of CBP