Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223.
Overview
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199 P. R. China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi 541199 P. R. China
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi 541199 P. R. China
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan 610041 P. R. China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, Weifang, 261031 P. R. China
- The Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001 P. R. China
- The Second Clinical College of Guilin Medical University, Guilin, Guangxi 541199 P. R. China
Abstract
High glucose impairs cognitive function in type 2 diabetes, but the underlying mechanism is unclear. In this study, guided by lactylome analysis, we reveal that high glucose induces LRPPRC K223 lactylation in hippocampal neurons by upregulating lactyltransferase AARS2, which weakens LRPPRC-SLIRP binding, reduces mitochondrial mRNA stability, subsequently leads to mitochondrial dysfunction, and ultimately results in neuronal apoptosis and cognitive decline. Notably, a novel short peptide designed to competitively inhibit LRPPRC K223 lactylation remarkably ameliorates cognitive impairment in diabetic mice. Moreover, through a large prospective cohort study, elevated plasma LRPPRC K224 lactylation (the human homolog of mouse LRPPRC K223) was identified as an independent predictor of cognitive impairment in type 2 diabetes patients. This work uncovers a key mechanism linking high glucose-induced lactylation to mitochondrial dysfunction and neuronal apoptosis, offering new molecular targets for prevention and treatment of diabetes-related cognitive impairment.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE201644, at NCBI GEO; found in the resources table
Other data links
- ebi.ac.uk/
biostudies/ , EMBL-EBI; found in the text, “Author contributions”sourcedata
Data availability
This study includes no data deposited in external repositories. No unique datasets or codes were generated, and all other data can be made available from the authors on reasonable request.
The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_103
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 29 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 2 keywords, 12 MeSH terms, 8 funders, 62 references, 17 RRIDs.
Cite
This paper
Xu, J., Hao, Y., Cao, J., Yang, X., Gao, Y., Sun, X., Nie, R., Zhong, Q., Zhong, Y., Zhong, J., & Zheng, T. (2026). Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223. EMBO molecular medicine, 18(6), 2038-2061. https://
BibTeX
@article{xu2026hyperglyc
author = {Xu, Jingxi and Hao, Yuqi and Cao, Jingxue and Yang, Xing and Gao, Yun and Sun, Xiaodong and Nie, Rongrong and Zhong, Qiongsui and Zhong, Yuanmei and Zhong, Junjia and Zheng, Tianpeng},
title = {{Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223}},
journal = {EMBO molecular medicine},
year = {2026},
month = apr,
volume = {18},
number = {6},
pages = {2038--2061},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/
url = {https://
pmid = {41942754},
pmcid = {PMC13269535}
}
RIS
TY - JOUR
AU - Xu, Jingxi
AU - Hao, Yuqi
AU - Cao, Jingxue
AU - Yang, Xing
AU - Gao, Yun
AU - Sun, Xiaodong
AU - Nie, Rongrong
AU - Zhong, Qiongsui
AU - Zhong, Yuanmei
AU - Zhong, Junjia
AU - Zheng, Tianpeng
TI - Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/
VL - 18
IS - 6
SP - 2038
EP - 2061
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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