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journal article·2026-06Open access

Kinsenoside Targets IDH1 to Restore Microglial Immune‐Metabolic Homeostasis for Alzheimer's Disease Therapy

Qianqian Li, Yajin Liao, Yan‐bo Zhao, Hongxing Wu, Tong Jin, Shuoshuo Li, Yuhan Liu, Peng Li, Songying Ouyang, Zekai Li, YuTing Xia, Qian Hua, Rui‐Yuan Pan, Zengqiang Yuan

Advanced Science· Volume 13· Issue 36
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Abstract

ABSTRACT Dysregulated tricarboxylic acid (TCA) cycle activity is increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, yet the mechanistic underpinnings of the relationship remain unclear. Here, we identify isocitrate dehydrogenase 1 (IDH1), a key enzyme in the TCA cycle, as a critical pathogenic driver of AD in microglia. IDH1 expression was markedly upregulated in microglia from both AD patients and 5×FAD mice. Elevated IDH1 promoted excessive cytosolic citrate consumption, which restricted citrate shuttling into mitochondria and impaired mitochondrial TCA cycle function. This citrate metabolic imbalance further disrupted epigenetic regulation, thereby exacerbating AD‐related pathological processes. Using structure‐based screening and co‐crystallization analysis, we identified Kinsenoside (KIN), a natural small molecule, as a selective competitive inhibitor of IDH1 that binds to its isocitrate‐binding pocket. Targeting IDH1 with KIN inhibited its activity, which restored intracellular citrate distribution, reactivated mitochondrial TCA cycle flux, and reestablished metabolic homeostasis. Notably, this intervention not only attenuated neuroinflammation but also reduced β‐amyloid (Aβ) deposition and significantly improved cognitive performance in 5×FAD mice. Collectively, our findings establish IDH1‐mediated metabolic dysregulation as a pivotal pathogenic mechanism in AD and highlight KIN as a promising therapeutic candidate by targeting microglial IDH1 to restore metabolic and functional homeostasis.
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Research context

Materials processing

OpenAlex topics: Neuroinflammation and Neurodegeneration Mechanisms · Alzheimer's disease research and treatments · Ginseng Biological Effects and Applications

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

The Brain Science Center Beijing Institute of Basic Medical Sciences Beijing China

Department of Neurology The Second Affiliated Hospital Hengyang Medical School University of South China Hengyang China

NHC Key Laboratory of Neurodegenerative diseases (University of South China) Hengyang China

Key Laboratory of Microbial Pathogenesis and Interventions of Fujian Province University the Key Laboratory of Innate Immune Biology of Fujian Province Biomedical Research Center of South China College of Life Sciences Fujian Normal University Fuzhou China

Key Laboratory of Mental Health of the Ministry of Education Guangdong‐Hong Kong‐Macao Greater Bay Area Center for Brain Science and Brain‐Inspired Intelligence Guangdong‐Hong Kong Joint Laboratory for Psychiatric Disorders Guangdong Province Key Laboratory of Psychiatric Disorders Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases Department of Neurobiology School of Basic Medical Sciences Southern Medical University Guangzhou China

School of Life Sciences Beijing University of Chinese Medicine Beijing China

School of Traditional Chinese Medicine Tianjin University of Traditional Chinese Medicine Tianjin China

College of Basic Sciences College of Basic Sciences Shanxi Agricultural University Jinzhong China

Key Laboratory of Clinical Neurology (Hebei Medical University) Ministry of Education Shijiazhuang Hebei China

The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology Shanxi University of Chinese Medicine Jinzhong China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Natural Science Foundation of Guangdong Province

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