ArticleCirculation research2025
Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.
Article in Circulation research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- LGR6 couples maresin 1 signaling to glycolytic flux and protein lactylation for the rescue of diabetic cardiomyopathy.Journal of diabetes investigation · 2026Article
- PDK4-Associated Metabolic Reprogramming Contributes to Lactate Accumulation and Parthanatos-Related Changes in Septic Cardiomyocytes.Cardiovascular drugs and therapy · 2026Article
- BGP-15 ameliorates sepsis-induced cardiomyopathy via SIRT3/SOD2-associated antioxidant signaling and suppression of myocardial inflammation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Beyond the Pump: Unravelling Immunometabolic Crosstalk and Organelle Dynamics in Sepsis-Induced Cardiomyopathy.Journal of cardiovascular translational research · 2026Article
- Epigenetic Mechanisms in Sepsis-Induced Cardiomyopathy: From Pathophysiology to Therapeutic Targets.International journal of molecular sciences · 2026Review
- Multiple organ dysfunction syndrome: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Lactylation landscape of mitochondrial proteins in myocardial infarction.Redox biology · 2026Article
- Mechanistic Studies of Lactate in Heart Failure: From Metabolic Biomarker to Therapeutic Target.Reviews in cardiovascular medicine · 2026Review
- mRedox biology · 2026Review
- A Novel SIRT1 Activator Hydroxygenkwanin Alleviates Osteoporosis by Inhibiting Ferroptosis and Lactylation in Skeletal Stem/Progenitor Cells.Antioxidants (Basel, Switzerland) · 2026Article
- Lactylation landscape of mitochondrial proteins in myocardial infarction.bioRxiv : the preprint server for biology · 2026Article
- Shengmai San Ameliorates High-Glucose-Induced Calcium Homeostasis Imbalance via Improving Energy Metabolism in Neonatal Rat Cardiomyocytes.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Retrospective Cohort Analysis of TyG, TyG-SI, and TyG-Lac Indices as Predictors of 360-Day Mortality in Critically Ill Ischemic Stroke Patients.Journal of clinical medicine · 2026Article
- Progress of Research on the Metabolic Regulation of Lactylation in Muscle Tissues and Its Disease Associations.Biomolecules · 2026Review
- Immunometabolic reprogramming and glycolysis-associated signatures in sepsis: insights from single-cell RNA sequencing and machine learning.Frontiers in immunology · 2026Article
- Protein lactylation in myocardial ischemia-reperfusion injury: mechanisms and therapeutic potential.Frontiers in cardiovascular medicine · 2026Review
- c-Myc: an emerging participant in heart failure.Frontiers in cardiovascular medicine · 2026Review
- Linking Metabolic and Mitochondrial Stress to Regulated Cell Death and Inflammatory Organ Injury in Sepsis.Journal of inflammation research · 2026Review
- Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury.Frontiers in immunology · 2026Review
- Frontiers in the diagnosis and treatment of sepsis-induced cardiomyopathy: current status and prospects.Frontiers in cardiovascular medicine · 2026Review
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15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSerum lactate levels are used to evaluate tissue hypoxia and predict outcomes in cases of sepsis and septic shock. Lactate can participate in a posttranslational modification known as lactylation. Myocardial depression during sepsis and septic shock is common. Here, we investigated the role of lactate in sepsis-induced myocardial depression.
methodsSeptic myocardial depression in rats was induced by lipopolysaccharide administration or cecal ligation and puncture. Lactylation and protein profiles of heart tissues from the control and lipopolysaccharide groups were analyzed using proteomic analysis. Lactylation of the HADHA (trifunctional enzyme subunit alpha) at K166 and K728 was detected in septic heart tissues and lipopolysaccharide-induced cultured cells. Mutation of K166 and K728 HADHA were used to clarify the effects of HADHA lactylation on mitochondrial function, ATP production, energy metabolism, and heart function. Transcriptomic and metabolomic analyses were used to identify differentially expressed genes and differential metabolites in H9c2 (rat cardiomyoblast cell line) cells.
resultsWe identified 1127 lysine lactylation sites, with 83 differentially lactylated lysine sites. By integrating multifeature hybrid learning and protein language models, we identified lactylation at K166 and K728 of the HADHA as functionally important. We confirmed that lactylation at these sites was influenced by lactate levels and inhibited the HADHA activity, which disturbed mitochondrial function, ATP production, and energy metabolism. This reduction in the contraction force of cardiomyocytes can influence heart function in vitro and in vivo. Furthermore, this study revealed that sirtuin 1 and sirtuin 3 regulated the lactylation of HADHA at K166 and K728.
conclusionsThis study reveals the significant impact of lactylation on cardiomyocyte metabolism. Lactate-induced HADHA lactylation disturbs cardiomyocyte mitochondrial function and metabolism and promotes sepsis-induced cardiac dysfunction. These findings inform the development of new therapeutic targets for sepsis-induced myocardial depression.
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