AI-assisted discovery of an ABCA1/ABCG1 activator for restoring mitophagy and mitigating Alzheimer’s pathology

Abstract Defective mitophagy is a key pathological risk of Alzheimer’s disease (AD), yet available pharmacological agents capable of restoring mitophagy remain clinically limited, largely due to the lack of tools for drug screening and target identification. To address this, we introduce an integrated platform with three novel artificial intelligence (AI)-enabled approaches—the phenotype-based screening model ‘CellAutoFM’, the drug-likeness predictor ‘ADMET Ranker’, and the target deconvolution method ‘PROCAT’. Using this platform together with wet lab validation, Crassifolin A (JGX-1) is identified as a potent natural product-derived mitophagy inducer; structurally, JGX-1 directly binds to ATP-binding cassette sub-family A member 1 (ABCA1) and sub-family G member 1 (ABCG1), triggering enhanced cholesterol efflux which activates PINK1/Parkin-dependent mitophagy. In both in vitro and in vivo AD laboratory models, JGX-1 reduces amyloid-β and Tau pathologies in an autophagy/mitophagy-dependent manner as these benefits are dramatically blunted with key mitophagy genes knocked down. Collectively, we provide an open-access, reproducible AI-assisted platform for rapid compound screening, drug-likeness evaluation, and potential target prediction to advance drug discovery. Through this paradigm, we unveil modulating the ABCA1/ABCG1-mediated cholesterol-mitophagy pathway as a promising anti-AD strategy, with a novel drug candidate JGX-1 identified.

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Publication Details

Journal
Molecular Neurodegeneration
Published
2026-10-07
DOI
https://doi.org/10.1186/s13024-026-00998-2
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
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article

AI-assisted discovery of an ABCA1/ABCG1 activator for restoring mitophagy and mitigating Alzheimer’s pathology

Haodong Xu, Haiyi Zhang, Jianying Zhang, Xuefeng Zhou et al.
Molecular Neurodegeneration
Alzheimer's disease research and treatments
article

AI-assisted discovery of an ABCA1/ABCG1 activator for restoring mitophagy and mitigating Alzheimer’s pathology

Haodong Xu, Haiyi Zhang, Jianying Zhang, Xuefeng Zhou, Zhangming Niu, Wenfan Wu, Evandro Fei Fang, Heling Wang, Guisi Chen, Shiqi Zhang, Fang Shi, Guobing Chen, Junping Pan, Lingyan Mao, Qiwei Cai, Guocai Wang, Zehuan Chen, Zhipeng Ling, Hongming Chen, Yubo Zhang, Shenglong Deng, Qing Tang, Guang Yang, Junliang Li, Yuehao Huang, Fei Xiao, Xianglu Xiao
article en

Abstract

Abstract Defective mitophagy is a key pathological risk of Alzheimer’s disease (AD), yet available pharmacological agents capable of restoring mitophagy remain clinically limited, largely due to the lack of tools for drug screening and target identification. To address this, we introduce an integrated platform with three novel artificial intelligence (AI)-enabled approaches—the phenotype-based screening model ‘CellAutoFM’, the drug-likeness predictor ‘ADMET Ranker’, and the target deconvolution method ‘PROCAT’. Using this platform together with wet lab validation, Crassifolin A (JGX-1) is identified as a potent natural product-derived mitophagy inducer; structurally, JGX-1 directly binds to ATP-binding cassette sub-family A member 1 (ABCA1) and sub-family G member 1 (ABCG1), triggering enhanced cholesterol efflux which activates PINK1/Parkin-dependent mitophagy. In both in vitro and in vivo AD laboratory models, JGX-1 reduces amyloid-β and Tau pathologies in an autophagy/mitophagy-dependent manner as these benefits are dramatically blunted with key mitophagy genes knocked down. Collectively, we provide an open-access, reproducible AI-assisted platform for rapid compound screening, drug-likeness evaluation, and potential target prediction to advance drug discovery. Through this paradigm, we unveil modulating the ABCA1/ABCG1-mediated cholesterol-mitophagy pathway as a promising anti-AD strategy, with a novel drug candidate JGX-1 identified.

Molecular Neurodegeneration
Sun Yat-sen University (CN), Jinan University (CN), University of Oslo (NO), Guangdong Pharmaceutical University (CN), Akershus University Hospital (NO), Guangzhou Women and Children Medical Center (CN), Zhongnan Hospital of Wuhan University (CN), Imperial College London (GB), Huazhong University of Science and Technology (CN), Guangzhou Medical University (CN)
Openalex Percentile: Top 13%
Alzheimer's disease research and treatments
DOIOpen Access PDFOpenAlex
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