ArticleJournal of advanced research2025
H4K12 lactylation potentiates mitochondrial oxidative stress via the Foxo1 pathway in diabetes-induced cognitive impairment.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Lactate Signal: Modulator of Cellular Energy Production and Anabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lactate as a metabolic-epigenetic hub in neurological disorders.Metabolic brain disease · 2026Review
- Identification of a Lactylation-Related Gene Signature and Candidate Biomarkers for Dilated Cardiomyopathy.Journal of cellular and molecular medicine · 2026Article
- FOXO family and neurodegenerative diseases: Mechanisms of action and therapeutic potential.Redox biology · 2026Review
- Research Progress on Downstream Mechanisms of Glucose Metabolic Reprogramming and Its Role in the Occurrence and Progression of Type 2 Diabetes Mellitus.Biomedicines · 2026Review
- Lactate-Primed NETosis Modulates Hepatic Regeneration During Acute Liver Failure via the TLR9/KLF15/AJUBA Axis.Cell proliferation · 2026Article
- Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review).International journal of molecular medicine · 2026Review
- Astrocytic GSTM2-STAT3 interaction ameliorates the diabetes associated cognitive dysfunction via targeting mitochondrial defects and oxidative stress.Redox biology · 2026Article
- CTNNB1 Genetic Variation and Its Interaction With DLK1 in Type 2 Diabetes Mellitus.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.International journal of molecular sciences · 2026Review
- AQP1 is Involved in NLRP3-Related Microglial Polarization and Cognitive Impairment in Chronic Sleep Deprivation.Inflammation · 2026Article
- Integrative Multi-Analysis Identifies METTL3-Regulated FGF19 and H6PD as Candidate Targets in Diabetic Cognitive Impairment.Biomolecules · 2026Article
- Beyond a metabolite: lactate and lactylation in lung diseases.Respiratory research · 2026Review
- Research Progress on Pathology, Molecular Mechanisms, and Intervention Strategies of Cognitive Dysfunction Associated with Type 2 Diabetes.International journal of general medicine · 2026Review
- β-Hydroxybutyrate-induced mitochondrial dysfunction and oxidative stress in BMSCs are ameliorated by mitophagy activation.Frontiers in cell and developmental biology · 2026Article
- Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders.Current research in microbial sciences · 2026Review
- Lactate and cognition: a dual modulator.Frontiers in molecular neuroscience · 2026Review
- Perioperative neurocognitive disorders as a neuroimmune landscape disorder: microglial priming, state heterogeneity, and time-dependent neuroinflammation.Frontiers in immunology · 2026Review
- Protein lactylation in Alzheimer's disease: bridging metabolism, pathology, and therapeutic opportunity.Frontiers in aging neuroscience · 2026Review
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsTo investigate the role and potential mechanisms of H4K12 lactylation modifications in diabetes-related cognitive impairment (DACD).
methodsBehavioral tests, HE staining, and immunohistochemistry were employed to assess cognitive function and the extent of brain tissue injury. Metabolomics and proteomics were applied to profile the metabolic regulatory network. We measured lactic acid and Pan-Kla levels in the brains of T2DM mice and high glucose-treated microglia. CUT&Tag technology was utilized to identify genes regulated by H4K12la. Small interfering RNA (siRNA) sequences and adeno-associated viruses (AAVs) were used to knock down key components in signaling pathways, evaluating the impact of histone lactylation on microglial polarization.
resultsLactic acid levels were significantly higher in the brains of T2DM mice and high glucose-treated microglia compared to controls, leading to an increase in pan histone lysine lactylation (Kla). We found that lactate directly induced an increase in H4K12la. CUT&Tag analysis revealed that elevated H4K12la activates the FOXO1/PGC-1α signaling pathway by enhancing binding to the FOXO1 promoter, promoting mitochondrial oxidative stress.
conclusionThis study demonstrated that elevated H4K12la directly activates the FOXO1 signaling pathway, promoting oxidative stress and contributing to DACD phenotypes.
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