ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
The Lactate-Primed KAT8‒PCK2 Axis Exacerbates Hepatic Ferroptosis During Ischemia/Reperfusion Injury by Reprogramming OXSM-Dependent Mitochondrial Fatty Acid Synthesis.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
- Lactate metabolism and protein lactylation in programmed cell death: From novel mechanism to therapeutic strategies in human diseases.Clinical and translational medicine · 2026Review
- Integration of Single-Cell and Bulk RNA Sequencing Data to Identify Lactylation-Related Gene Signatures in Hepatic Ischemia-Reperfusion Injury Using Machine Learning Algorithms.International journal of molecular sciences · 2026Article
- KAT8-mediated epigenetic modifications: Physiological functions, heterogeneity in disease, and advances in targeted development.iScience · 2026Review
- The KAT8-CDK1 K33 acetylation axis drives doxorubicin resistance by suppressing ferroptosis and apoptosis in breast cancer.Cell death & disease · 2026Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- Lactylation landscape of mitochondrial proteins in myocardial infarction.Redox biology · 2026Article
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.Signal transduction and targeted therapy · 2026Review
- HSP90AA1 inhibits the Jun/Fos pathway to rescue hepatocytes from cuproptosis during ischemia-reperfusion injury.Clinical and experimental medicine · 2026Article
- Lactylation-regulated ferroptosis: mechanisms, disease associations, and therapeutic strategies.Archives of pharmacal research · 2026Review
- Lactylation landscape of mitochondrial proteins in myocardial infarction.bioRxiv : the preprint server for biology · 2026Article
- Lactate metabolism and lactylation: Therapeutic and pre-clinical implications in neovascularization in peripheral artery disease.Journal of pharmaceutical analysis · 2026Review
- Lactylation and acetylation: parallel paths, divergent deeds, and research dilemmas.Journal of translational medicine · 2026Review
- Protein Lactylation in Liver Disease: A Comprehensive Review.Expert reviews in molecular medicine · 2026Review
- Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review).International journal of molecular medicine · 2026Review
- Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review).International journal of molecular medicine · 2026Review
- Glycolysis enzymes and cellular lactylation in tumour.Clinical and translational medicine · 2026Review
- Role of lactylation modification in regulating lytic cell death.Frontiers in oncology · 2026Review
- AARS1-mediated AKR1B10 lactylation stabilizes an aerobic glycolysis-positive feedback loop to drive lenvatinib resistance in hepatocellular carcinoma.Clinical and translational medicine · 2026Article
- Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia-reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate-primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene-edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin-mediated polyubiquitination of 3-oxoacyl-ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia-mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT.
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