High glucose impairs cognitive function by inducing lipid droplet accumulation through lactylation of HSD17B10 at K105

  • Cell Rep. 2026 Jun 23;45(6):117550. doi: 10.1016/j.celrep.2026.117550.
Jingxi Xu  1 ,  Jingxue Cao  1 ,  Xing Yang  2 ,  Yuqi Hao  2 ,  Yun Gao  3 ,  Xiaodong Sun  4 ,  Rongrong Nie  5 ,  Qiongsui Zhong  6 ,  Yuanmei Zhong  7 ,  Sha Leng  7 ,  Lu Xu  7 ,  Chunxia Nie  7 ,  Tianpeng Zheng  8
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China.
  • 4. Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, Weifang 261031, P.R. China.
  • 5. The Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China.
  • 6. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of 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.
  • 7. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China.
  • 8. 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. Electronic address: [email protected].
PMID: 42275213 DOI: 10.1016/j.celrep.2026.117550
Abstract

High glucose is known to impair cognitive function in individuals with type 2 diabetes, though the precise mechanisms remain unclear. In this study, guided by lactylome analysis, we demonstrate that high glucose induces HSD17B10 K105 lactylation in hippocampal neurons by upregulating lactyltransferase Aars1, which reduces HSD17B10 enzyme activity, subsequently resulting in impaired breakdown and excessive accumulation of lipid droplets, and ultimately leading to neuronal Apoptosis and cognitive decline. Notably, a short peptide that competitively inhibits HSD17B10 K105 lactylation remarkably mitigates cognitive impairment in diabetic mice. Furthermore, results from a large-scale prospective cohort study reveal that elevated plasma HSD17B10 K105 lactylation serves as an independent predictor of cognitive dysfunction in patients with type 2 diabetes. These findings uncover a critical pathway linking high glucose-induced lactylation to lipid accumulation and neuronal cell death, highlighting promising molecular targets for the prevention and treatment of diabetes-associated cognitive impairment.

Keywords
CP: metabolism; CP: neuroscience; HSD17B10; cognitive impairment; diabetes; lactylation; lipid droplet.
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