H4K12 lactylation potentiates mitochondrial oxidative stress via the Foxo1 pathway in diabetes-induced cognitive impairment

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research Pub Date : 2025-02-16 DOI:10.1016/j.jare.2025.02.020

Ying Yang, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang

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Abstract

Aims

To investigate the role and potential mechanisms of H4K12 lactylation modifications in diabetes-related cognitive impairment (DACD).

Methods

Behavioral 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.

Results

Lactic 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.

Conclusion

This study demonstrated that elevated H4K12la directly activates the FOXO1 signaling pathway, promoting oxidative stress and contributing to DACD phenotypes.

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来源期刊

Journal of Advanced Research Multidisciplinary-Multidisciplinary

CiteScore

21.60

自引率

0.90%

发文量

280

审稿时长

12 weeks

期刊介绍： Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.