Shuqin Cao

• Lautrup, Sofie Hindkjær; Cao, Shuqin; Long, Xi; Liu, Bonnie Hei Man; Doncel, Beatriz Escobar & Ferrante, Aristide [Show all 16 contributors for this article] (2026). A combined artificial intelligence–wet lab approach identifies a pivotal role of the NAD+–mitophagy axis on aging and neurodegeneration. Alzheimer's & Dementia. ISSN 1552-5260. 22(8). doi: 10.1002/alz.71680. Full text in Research Archive Show summary

  Introduction: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+–mitophagy axis contributes to brain aging and neurodegeneration. Methods: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+–mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons. Results: The NAD+–mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology. Discussion: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+–mitophagy axis as a central player in brain aging and AD.

• Cao, Shuqin; Jiménez-Loygorri, Juan Ignacio; Boya, Patricia & Fang, Evandro F. (2026). The ‘mitochondrial guardian’ α-amyrin links colourful fruit consumption to cognitive resilience. Autophagy. ISSN 1554-8627. p. 3–3. doi: 10.1080/15548627.2026.2664599. Full text in Research Archive
• Cao, Shuqin; Jiménez-Loygorri, Juan Ignacio; Qiu, Yunguang; Kang, You Jung; Do, Khanh Van & Smith, Annabel E. [Show all 37 contributors for this article] (2026). The Mitochondrial Guardian α-Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK-SARM1-ULK1 Axis. Advanced Science. 13(24). doi: 10.1002/advs.202512374. Full text in Research Archive Show summary

  ABSTRACT High consumption of colorful fruits and vegetables correlates with low dementia risk, but the exact molecules and the underlying biological mechanisms governing their bioactive profiles are largely unknown. Using a 10‐year observational cohort study coupled with an AI‐driven systems pharmacology platform, we identified a natural triterpenoid compound found in colorful fruits and vegetables, α‐Amyrin (αA), as a therapeutic candidate for Alzheimer's disease (AD). The efficacy of αA in treating the symptoms of AD, such as Tau tangles, damaged mitochondria, and memory loss, was examined using cross‐species models; αA retained memory in AD‐like animal models while also strongly inhibiting Tau pathology, especially p‐Tau217, in a cellular ‘Tau seeding’ system and in Tau[P301S] mice, followed by validation using a human 3D microfluidic system. At molecular level, αA is a robust mitochondrial regulator, enhancing mitochondrial stress resilience and activation of mitophagy. Mechanistically, αA inhibits dual leucine zipper kinase (DLK), leading to the inhibition of DLK‐Sterile Alpha and TIR Motif Containing 1 (SARM1)‐dependent neurodegeneration; this inhibition frees unc‐51 Like Autophagy Activating Kinase 1 (ULK1) from the ULK1‐SARM1 complex, allowing it to participate in autophagy/mitophagy. αA also shows strong translational potential with a 10.1 h half‐life and the ability to cross the blood‐brain barrier. Our results indicate that αA may act as a mitochondrial guardian against AD via modulating the DLK‐SARM1‐ULK1‐autophagy/mitophagy axis while further preclinical and clinical studies are warranted.

• Lagartos, Maria Jose Donate; Doncel, Beatriz Escobar; Zhang, Shi-qi; Pan, Junping; González, Noemí Villaseca & Anisimov, Aleksander [Show all 22 contributors for this article] (2026). Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+. Brain. ISSN 0006-8950. 149(4), p. 1208–1223. doi: 10.1093/brain/awaf261. Full text in Research Archive Show summary

  Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer’s disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.

• Li, Ang; Xiao, Xianglu; Liu, Guopan; Li, Krinos; Ling, Yixia & Deng, Shenglong [Show all 14 contributors for this article] (2026). Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β–TFEB signaling axis. Pharmacological Research. ISSN 1043-6618. 227. doi: 10.1016/j.phrs.2026.108172. Full text in Research Archive
• Lin, Jin Yi; Huang, Ze Bo; Zhang, Shi-qi; Wu, Yong; Cheng, Ling Jun & Gao, Xiangzheng [Show all 17 contributors for this article] (2026). STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels. Cell reports. 45(4). doi: 10.1016/j.celrep.2026.117183. Full text in Research Archive
• Ai, Ruixue; Mao, Lipeng; Jin, Xurui; Campos-Marques, Carlos; Zhang, Shi-qi & Pan, Junping [Show all 33 contributors for this article] (2025). NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C. Science Advances. 11(45). doi: 10.1126/sciadv.ady9811. Full text in Research Archive Show summary

  Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau–bearing mice. We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.

• Li, Ang; Huang, Sen; Cao, Shuqin; Lin, Jinyi; Zhao, Linping & Yu, Feng [Show all 23 contributors for this article] (2025). Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy. EMBO Molecular Medicine. ISSN 1757-4676. 17(11), p. 3139–3173. doi: 10.1038/s44321-025-00323-2. Full text in Research Archive Show summary

  Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1–Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1–Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.

• Feng, Yayan; Cao, Shuqin; Shi, Yi; Sun, Anna; Flanagan, Margaret E. & Leverenz, James B. [Show all 12 contributors for this article] (2025). Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 21(2). doi: 10.1002/alz.14595. Full text in Research Archive Show summary

  INTRODUCTION Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. METHODS We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies. RESULTS We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model. DISCUSSION Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation.

• Wang, Heling; Zhang, Jianying; Cao, Shuqin; Lagartos, Maria Jose Donate; Zhang, Shi-qi & Lautrup, Sofie Hindkjær [Show all 10 contributors for this article] (2024). A luminescent-based protocol for NAD+/NADH detection in C. elegans, mice, and human whole blood. STAR Protocols. 5(4). doi: 10.1016/j.xpro.2024.103428. Full text in Research Archive Show summary

  Here, we present a NAD+/NADH detection assay for evaluating NAD+, NADH, and NAD+/NADH ratio across diverse biological models, including Caenorhabditis elegans, mouse muscle tissue, mouse whole blood, and human whole blood. We describe steps for sample collection and preparation from different models as well as detection and calculation of NAD+ and NADH levels. This protocol is applicable for quantifying cellular/tissue NAD+ and NADH levels across different biological models.

• Cao, Shuqin; Aman, Yahyah; Fang, Fei & Tencomnao, Tewin (2022). P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer’s Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway. Molecular Neurobiology. ISSN 0893-7648. 59(9), p. 5612–5629. doi: 10.1007/s12035-022-02904-5. Full text in Research Archive
• Xie, Chenglong; Zhuang, Xu-Xu; Niu, Zhangming; Ai, Ruixue; Lautrup, Sofie Hindkjær & Zheng, Shuangjia [Show all 29 contributors for this article] (2022). Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nature Biomedical Engineering. 6(1), p. 76–93. doi: 10.1038/s41551-021-00819-5. Full text in Research Archive Show summary

  Abstract A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

• Aman, Yahyah; Cao, Shuqin & Fang, Fei (2020). Iron out, mitophagy in! A way to slow down hepatocellular carcinoma. EMBO Reports. ISSN 1469-221X. 21(11), p. e51652–e51652. doi: 10.15252/embr.202051652. Full text in Research Archive

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• Li, Ang; Cao, Shuqin; Fang-Stavem, Fei & Su, Huanxing (2025). Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2025.2610450. Full text in Research Archive
• Cao, Shuqin; Wang, Heling; Palikaras, Konstantinos; Tavernarakis, Nektarios & Fang, Fei (2023). Chemotaxis assay for evaluation of memory-like behavior in wild-type and Alzheimer's-disease-like C. elegans models. STAR Protocols. 4(2). doi: 10.1016/j.xpro.2023.102250. Full text in Research Archive
• Schmauck-Medina, Tomás Alejandro; Molière, Adrian; Lautrup, Sofie Hindkjær; Zhang, Jianying; Chlopicki, Stefan & Madsen, Helena Borland [Show all 21 contributors for this article] (2022). New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging. 14(16), p. 6829–6839. doi: 10.18632/aging.204248. Full text in Research Archive Show summary

  Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the ‘old’ and ‘new’ hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

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