{"title":"PDK4-Associated Metabolic Reprogramming Contributes to Lactate Accumulation and Parthanatos-Related Changes in Septic Cardiomyocytes.","authors":"Shaodong Yang, Cairong Yan, Zhenwei Xu, Tianbao Huang, Jintu Chen, Jingfa Zhu","doi":"10.1007/s10557-026-07970-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Sepsis-related myocardial injury (SRMI) is characterized by metabolic reprogramming and cardiomyocyte death, but the relationship between these processes remains unclear. This study investigated the association between pyruvate dehydrogenase kinase 4 (PDK4)-related metabolic dysregulation and parthanatos-related changes in SRMI.</p><p><strong>Methods: </strong>SRMI was modeled using cecal ligation and perforation in mice and lipopolysaccharide-stimulated H9c2 cells. Myocardial injury, metabolic alterations, mitochondrial dysfunction, and parthanatos-related changes were assessed using RNA sequencing, histopathology, transmission electron microscopy, biochemical assays, Western blotting, RT-qPCR, immunofluorescence, and flow cytometry. PDK4 was silenced using siRNA in LPS-stimulated H9c2 cells for functional validation.</p><p><strong>Results: </strong>PDK4 was significantly upregulated in septic myocardium. This change was accompanied by increased PDH phosphorylation, pyruvate and lactate accumulation, ATP depletion, and mitochondrial ultrastructural damage. PAR accumulation increased, NAD⁺ levels decreased, and AIF/MIF nuclear translocation was enhanced, indicating prominent parthanatos-related changes. In LPS-stimulated H9c2 cells, PDK4 knockdown decreased the p-PDH/PDH ratio and lactate levels while increasing ATP levels. PDK4 silencing also reduced PAR accumulation, increased NAD⁺ levels, and decreased AIF/MIF nuclear translocation.</p><p><strong>Conclusion: </strong>PDK4 contributes to metabolic dysregulation and parthanatos-related changes in septic cardiomyocytes. However, whether lactate directly mediates the relationship between PDK4 and parthanatos requires further rescue experiments.</p>","PeriodicalId":9557,"journal":{"name":"Cardiovascular Drugs and Therapy","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Drugs and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10557-026-07970-8","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Sepsis-related myocardial injury (SRMI) is characterized by metabolic reprogramming and cardiomyocyte death, but the relationship between these processes remains unclear. This study investigated the association between pyruvate dehydrogenase kinase 4 (PDK4)-related metabolic dysregulation and parthanatos-related changes in SRMI.
Methods: SRMI was modeled using cecal ligation and perforation in mice and lipopolysaccharide-stimulated H9c2 cells. Myocardial injury, metabolic alterations, mitochondrial dysfunction, and parthanatos-related changes were assessed using RNA sequencing, histopathology, transmission electron microscopy, biochemical assays, Western blotting, RT-qPCR, immunofluorescence, and flow cytometry. PDK4 was silenced using siRNA in LPS-stimulated H9c2 cells for functional validation.
Results: PDK4 was significantly upregulated in septic myocardium. This change was accompanied by increased PDH phosphorylation, pyruvate and lactate accumulation, ATP depletion, and mitochondrial ultrastructural damage. PAR accumulation increased, NAD⁺ levels decreased, and AIF/MIF nuclear translocation was enhanced, indicating prominent parthanatos-related changes. In LPS-stimulated H9c2 cells, PDK4 knockdown decreased the p-PDH/PDH ratio and lactate levels while increasing ATP levels. PDK4 silencing also reduced PAR accumulation, increased NAD⁺ levels, and decreased AIF/MIF nuclear translocation.
Conclusion: PDK4 contributes to metabolic dysregulation and parthanatos-related changes in septic cardiomyocytes. However, whether lactate directly mediates the relationship between PDK4 and parthanatos requires further rescue experiments.
期刊介绍：
Designed to objectively cover the process of bench to bedside development of cardiovascular drug, device and cell therapy, and to bring you the information you need most in a timely and useful format, Cardiovascular Drugs and Therapy takes a fresh and energetic look at advances in this dynamic field.
Homing in on the most exciting work being done on new therapeutic agents, Cardiovascular Drugs and Therapy focusses on developments in atherosclerosis, hyperlipidemia, diabetes, ischemic syndromes and arrhythmias. The Journal is an authoritative source of current and relevant information that is indispensable for basic and clinical investigators aiming for novel, breakthrough research as well as for cardiologists seeking to best serve their patients.
Providing you with a single, concise reference tool acknowledged to be among the finest in the world, Cardiovascular Drugs and Therapy is listed in Web of Science and PubMed/Medline among other abstracting and indexing services. The regular articles and frequent special topical issues equip you with an up-to-date source defined by the need for accurate information on an ever-evolving field. Cardiovascular Drugs and Therapy is a careful and accurate guide through the maze of new products and therapies which furnishes you with the details on cardiovascular pharmacology that you will refer to time and time again.
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