Research最新文献

{"title":"Prediction of Major Adverse Cardiovascular Events in Peripheral Artery Disease: Integrating Metabolomics and Proteomics for Risk Stratification.","authors":"Wenxin Zhao, Lingbing Meng, Sheng Yan, Peng Li, Youjing Sun, Yaming Guo, Bowen Zhang, Yifan Cao, Junhong Ren, Yongjun Li, Zuoguan Chen","doi":"10.34133/research.1229","DOIUrl":"https://doi.org/10.34133/research.1229","url":null,"abstract":"<p><p>Peripheral artery disease (PAD) confers elevated risk for major adverse cardiovascular events (MACE), yet accurate risk stratification remains a challenge, particularly among patients with advanced disease necessitating endovascular revascularization. This study aimed to improve the prediction of MACE in a clearly defined high-risk PAD population (hospitalized patients undergoing endovascular intervention) by identifying novel protein biomarkers and developing a robust risk model. We prospectively analyzed blood samples from 164 hospitalized PAD patients scheduled for endovascular revascularization, employing untargeted plasma proteomics and metabolomics. Differential protein and metabolite profiles were compared between patients with and without subsequent MACE. Several proteins, including MMP3, MMP19, and PRB2, were markedly elevated in patients who developed MACE. A proteomics-based risk model incorporating these biomarkers achieved high discriminative accuracy (area under the curve > 0.80) for identifying individuals at increased risk. Metabolomic profiling revealed additional pathway alterations, notably involving tryptophan and glycogen metabolism, which provided mechanistic insights into cardiovascular complications but were not directly incorporated into the prediction model. This study demonstrates that integrating protein biomarkers markedly improves risk stratification in advanced PAD patients undergoing surgical intervention. The findings offer promising tools for early detection and enable more personalized management for this high-risk subgroup, while also deepening understanding of disease pathophysiology. However, further validation in larger and more diverse prospective cohorts is warranted before these findings can be broadly applied in clinical practice.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1229"},"PeriodicalIF":10.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole-3-Carbaldehyde from <i>Limosilactobacillus reuteri</i> Boosts Chemotherapy Response in Diffuse Large B Cell Lymphoma by Blocking the Mechanistic Target of Rapamycin Pathway.","authors":"Zhengfeng Zhang, Congcong Li, Yuhan Tang, Bingrong Liu, Jingyu Wang, Leilei Kong, Wanwan Bao, Hurong Lai, Tingtao Chen, Jian Li","doi":"10.34133/research.1267","DOIUrl":"https://doi.org/10.34133/research.1267","url":null,"abstract":"<p><p>Diffuse large B cell lymphoma (DLBCL) presents a critical clinical challenge due to declining chemosensitivity and difficult-to-manage dose-limiting toxicities. Although gut microbiota modulation shows potential for \"toxicity reduction and efficacy enhancement\", its mechanism in DLBCL remains unclear. Comparative analysis revealed a marked reduction of beneficial bacteria in patients with DLBCL versus healthy volunteers, with a marked decrease in the abundance of core probiotics, particularly <i>Limosilactobacillus reuteri</i>. Fecal microbiota transplantation from healthy donors into DLBCL mouse models reduced tumor burden, improved chemosensitivity, and alleviated intestinal toxicity. A core probiotic strain, <i>L. reuteri</i> HG001, was isolated and shown to replicate these effects alone, with the tryptophan metabolite indole-3-carbaldehyde (ICAld) identified as the key component responsible for its adjunctive antitumor activity. Mechanistic studies demonstrated that ICAld exerts significant adjunctive antitumor effects both <i>in vitro</i> and <i>in vivo</i> in a dose-dependent manner in mouse models; it acts by activating the aryl hydrocarbon receptor (AHR)/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/reactive oxygen species (ROS) axis, inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway, promoting apoptosis, and synergizing with cyclophosphamide. An aryl hydrocarbon receptor antagonist reversed both the chemosensitizing and intestinal protective effects of <i>L. reuteri</i> HG001 and ICAld. This study elucidates a microbiota-mediated mechanism in DLBCL and supports <i>L. reuteri</i> HG001 as a probiotic adjuvant to enhance therapy while reducing toxicity.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1267"},"PeriodicalIF":10.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A General Kinematic Model for Multimodal Locomotion in Bioinspired Robots.","authors":"Zicun Hong, Junwen Fei, Weihua Li, Jun Yan, Junzhi Yu, Feng Tian, Yong Zhong","doi":"10.34133/research.1275","DOIUrl":"https://doi.org/10.34133/research.1275","url":null,"abstract":"<p><p>Locomotion in animals such as fish, snakes, inchworms, and octopuses exhibits a remarkable diversity, with each species utilizing distinct body morphologies and movement strategies. Currently, no existing kinematic model is capable of describing the full range of locomotion exhibited by these animals. Addressing this challenge holds important implications for both the study of biomechanics of animals and the development of bioinspired robots. In this work, we propose a general kinematic model that integrates the curvature equation with a nonlinear oscillator. Through parameter adjustments, its morphology can transition between the motions of various animals. It is the most versatile kinematic model to date for describing multimodal locomotion of animals so far as we know. By translating the general kinematic model into a motion control algorithm and combining it with virtual simulation, we create a motion optimization framework that substantially simplifies the complexity of multimodal control for bionic robots with diverse actuation mechanisms, thereby enhancing their maneuverability. Using fish locomotion as an example, we validate the methodology on an untethered multijoint robotic fish, successfully enabling the robotic fish to perform cruising and various fast turn motions, thereby demonstrating its effectiveness in guiding motion control. This work is believed to have laid the foundation for the study of bionic motion and bioinspired robots.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1275"},"PeriodicalIF":10.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Doping-Engineered Proangiogenic Nanozymes Orchestrate Ischemic Tissue Regeneration via Cytoprotection and Revascularization.","authors":"Huili Li, Xiaosheng Sheng, Chuandong Qiu, Dongmin Chen, Lefeng Su, Qishu Jin, Xin Gong, Yanxin Zhang, Zhaoxu Meng, Xin Li, Hangbin Xia, Chunlong Zhang, Zhen Zeng, Xiaoting Chen, Jiehao Chen, Yiren Jiao, Jiang Chang, Yumei Que, Zhaowenbin Zhang, Chen Yang, Wenzhong Li","doi":"10.34133/research.1260","DOIUrl":"https://doi.org/10.34133/research.1260","url":null,"abstract":"<p><p>Effective therapy for ischemic diseases requires not only timely restoration of perfusion but also protection of ischemic tissues from secondary insults, particularly oxidative-stress-induced injury. Here, we propose the concept of \"proangiogenic nanozymes\" and develop an efficient screening platform by doping angiogenic elements (Mg, Co, Cu, Zn, Sr, or Eu) into an archetypal antioxidative nanozyme, Prussian blue. Systematic assessment of catalytic activity and proangiogenic performance identified Cu-doped Prussian blue (CuPB) as the lead candidate. In addition to efficiently decomposing multiple reactive oxygen species, thereby attenuating oxidative stress, reducing apoptosis, and protecting ischemic tissues from secondary injury, CuPB nanozymes also stimulated angiogenesis, thereby accelerating tissue repair. In murine models of hind limb ischemia and myocardial infarction, CuPB conferred therapeutic benefits after both local and systemic administration, underscoring its translational potential. This proangiogenic nanozyme strategy offers an integrated and effective approach to ischemic tissue regeneration, bridging catalytic nanomedicine and vascular repair.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1260"},"PeriodicalIF":10.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13121891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type I Framework Complex: Photocontrolled Superoxide Anion Generator.","authors":"Zehao Jing, Yingying Zhang, Yingnan Wu, Xiaoqiang Chen, Meizhen Yin, Mingle Li, Xiaojun Peng","doi":"10.34133/research.1262","DOIUrl":"https://doi.org/10.34133/research.1262","url":null,"abstract":"<p><p>Photodynamic therapy (PDT) is a clinically approved therapeutic modality that uses photosensitizers (PSs) to generate reactive oxygen species (ROS) upon light irradiation, enabling disease treatment with minimal invasiveness and excellent spatiotemporal precision. Despite these advantages, conventional PDT is fundamentally constrained by the mismatch between its oxygen dependence and the intrinsically hypoxic tumor microenvironment, which markedly compromises therapeutic outcomes. In this context, type I PSs offer a promising solution because they can produce cytotoxic radicals through electron transfer pathways, thereby reducing dependence on oxygen (O₂) and improving efficacy under hypoxic conditions. Organic framework materials have recently emerged as powerful and versatile platforms for constructing type I PSs, owing to their programmable structures, high porosity, and efficient photoinduced charge separation and electron transfer. Importantly, the modular nature of these frameworks enables rational tuning of both structural motifs and compositional building blocks, allowing systematic regulation of light absorption, redox properties, and ROS generation pathways to maximize type I PDT performance. Moreover, organic frameworks can simultaneously function as nanocarriers for therapeutics, facilitating co-delivery and synergistic combinations (e.g., chemotherapy, immunotherapy, or catalytic therapies) that may achieve more durable and comprehensive tumor control. However, current studies remain fragmented, and there is still a lack of an integrated and mechanistically grounded overview that connects framework design principles with type I ROS generation mechanisms and performance optimization strategies. To address this unmet need, this review provides a comprehensive summary of the design strategies, mechanistic insights, and recent progress in organic framework-based type I PSs. We first outline the fundamental principles of type I photochemistry and the key physical and chemical processes underlying type I PDT. We then highlight rational design and modulation strategies to enhance optical properties, promote charge separation, and strengthen oxygen independence. Next, we summarize representative in vivo/in vitro disease models to demonstrate emerging diagnostic and therapeutic applications. Finally, we discuss current challenges and future opportunities for clinical translation, offering practical guidance for the development of next-generation phototherapeutic agents based on these innovative framework systems.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1262"},"PeriodicalIF":10.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Respiration to Secondary Metabolism: A Heme A Synthase-Mediated Regulatory Network Expands Indolizidine Chemical Space in Fungi.","authors":"Wei Bai, Guangzhi Dai, Junyang Ji, Qi Du, Meiling Ding, Wenbo Han, Hao Zhu, Xincun Wang, Wenying Zhuang, Renxiang Tan","doi":"10.34133/research.1236","DOIUrl":"https://doi.org/10.34133/research.1236","url":null,"abstract":"<p><p>In single-cell microbes, primary and secondary metabolism are synergistically integrated to support survival and environmental adaptation through the biosynthesis of structurally diverse and biologically active small molecules-known as secondary metabolites (SMs) or natural products, such as penicillin. However, the therapeutic potential of microbial SMs is often limited because their biosynthetic gene clusters remain silent or weakly expressed under laboratory conditions. In this study, we employed BioNavi-NP as a guide to identify heme A synthase (<i>Cl</i>HAS) as a novel metabolic link in <i>Curvularia lunata</i>, bridging primary and secondary metabolism. Surprisingly, inactivation of <i>Cl</i>HAS led to the diversification of its characteristic indolizidine alkaloids, yielding previously unreported molecular frameworks. Mechanistically, <i>Cl</i>HAS disruption impaired heme biosynthesis, thereby inducing oxidative stress that activated an uncharacterized basic-region leucine zipper transcription factor (A7370). A7370 binds specifically to a unique <i>cis</i>-element (ACGGCTGAC) in the promoter region of <i>cuaF</i>, a pathway-specific positive regulator of indolizidine alkaloid biosynthesis. This cascade regulation produces structurally unprecedented alkaloids, some of which show antibacterial activity equal or superior to the clinically prescribed drug, tinidazole, against a range of human pathogenic bacteria. Overall, this work reveals a conserved regulatory network that coordinates primary and secondary metabolism in fungi, providing new mechanistic insights into the complexity of fungal SM biosynthesis.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1236"},"PeriodicalIF":10.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NIR-Activated ICG-Loaded M2 Macrophage Exosomes Ameliorate Periodontitis via Targeting Infection Inflammation and Oxidative Stress.","authors":"Xincong Li, Xin Fu, Tianyu Zhang, Xiaofan Cheng, Hai Zhuang, Zhilei Mao, Shoushan Bu","doi":"10.34133/research.1207","DOIUrl":"https://doi.org/10.34133/research.1207","url":null,"abstract":"<p><p>Periodontitis is a chronic bacterial inflammatory disease. M2 macrophage-derived exosomes (M2-exos) possess targeted immunomodulatory abilities, but their role in mitigating oxidative stress (key for periodontitis treatment) remains unclear. In this study, we engineered M2-exos loaded with indocyanine green (ICG) (ICG@M2-exos) for the treatment of periodontitis. The constructed ICG@M2-exos effectively facilitated macrophage reprogramming from the M1 to the M2 phenotype, thereby resolving chronic inflammation and enhancing periodontal tissue repair. Under near-infrared irradiation, ICG conferred potent antibacterial efficacy against <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>). Simultaneously, the exosomes released from ICG@M2-exos mitigated oxidative stress and decreased the expression of proinflammatory factors in THP-1 cells through promoting M2 polarization. In a rat model of <i>P. gingivalis</i>-induced periodontitis, the sustained release of ICG@M2-exos markedly expedited periodontal bone regeneration, accompanied by elevated levels of anti-inflammatory cytokines. Collectively, ICG-engineered M2-exos represent a promising strategy for tackling inflammatory periodontal conditions. This study demonstrates the dual advantages of ICG@M2-exos in near-infrared-responsive antibacterial activity and immunomodulation that work synergistically, laying a solid foundation for future clinical applications.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1207"},"PeriodicalIF":10.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to \"Heterogeneity-Aware, Multiscale Annotation of Shared and Specific Neurobiological Signatures among Major Neurodevelopmental Disorders\".","authors":"Yunheng Diao, Yuanyuan Huang, Baoyuan Zhu, Minxin Guo, Wei Wang, Zhaobo Li, Wenhao Li, Heng Zhang, Jing Zhou, Xiaobo Li, Fengchun Wu, Kai Wu","doi":"10.34133/research.1256","DOIUrl":"https://doi.org/10.34133/research.1256","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.34133/research.1115.].</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1256"},"PeriodicalIF":10.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13106937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Explainable Deep Reinforcement Learning for Anomaly Detection in IoT-Enabled Metaverse Healthcare: Toward Trustworthy Cyber Threat Intelligence.","authors":"Jing Yang, Xu Xu, Muhammad Attique Khan, Ghassen Ben Brahim, Jamel Baili, Lip Yee Por, Congsheng Li","doi":"10.34133/research.1245","DOIUrl":"https://doi.org/10.34133/research.1245","url":null,"abstract":"<p><p>The dynamic metaverse paradigm integrates emerging technologies and offers transformative opportunities to enhance consumer healthcare applications through immersive, connected experiences. However, this paradigm faces substantial cybersecurity challenges, such as distributed denial-of-service attacks, probing, and port scanning. This undermines the trustworthiness and resilience of healthcare analytics frameworks. To address these threats, intrusion detection systems that support proactive anomaly detection are essential for securing metaverse-based healthcare applications. Conventional anomaly detection techniques face challenges such as low interpretability, suboptimal feature selection, class imbalance, and inefficient hyperparameter tuning. These challenges limit their reliability in practical cyber threat intelligence settings. To solve these challenges, this paper presents an anomaly-detection framework for Internet of Things-enabled metaverse healthcare environments. The proposed framework leverages an off-policy proximal policy optimization (PPO) algorithm that incorporates SHapley Additive exPlanations-based feature selection and class-specific reward adjustments to address imbalance. The reinforcement learning-based off-policy PPO enables adaptive, sample-efficient learning by leveraging prior experience during policy updates. The hyperparameters of the model are optimized using the Bayesian Optimization Hyperband algorithm to accelerate training and enhance performance. This optimization technique combines Bayesian search with the Hyperband method to improve efficiency and convergence during model tuning. The performance of our model is evaluated on NSL-KDD, MAWI, and CICIoT2023 datasets. The results depict that the model outperformed its contemporaries with state-of-the-art results where accuracy, F-measure, G-means, and area under the curve reached 88.005%, 87.271%, 87.986%, and 0.870; 92.184%, 88.992%, 89.738%, and 0.873; and 89.368%, 88.312%, 89.039%, and 0.836, respectively. The results confirm the effectiveness of the framework in cyber threat scenarios. They also show their potential for explainable, trustworthy intelligence in metaverse healthcare.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1245"},"PeriodicalIF":10.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myokine Cathepsin B as a Key Muscle-Brain Axis Regulator Mediates Treadmill-Running-Induced Hippocampal Neurogenesis and Cognitive Improvement in Mice.","authors":"Xuchang Zhou, Dongxue Wang, Huili Deng, Jianmin Guo, Xier Chen, Zhangyu Lin, Baolong Liu, Ruobing Zhao, Lu Gao, Xuan Yin, Yun Zhang, Yan Chen, Yajing Yang, Qingxian Li, Qu Shen, Jianguang Ji, Guoxin Ni","doi":"10.34133/research.1233","DOIUrl":"https://doi.org/10.34133/research.1233","url":null,"abstract":"<p><p>This study aimed to explore the impact of treadmill running at different intensities and durations on hippocampal neurogenesis and cognitive function in mice, with a focus on the interorgan communication mechanism mediated by the extracellular vesicle (EV) cargo cathepsin B (CTSB) via the muscle-brain axis. We define the intensity of treadmill running mice based on measurements of maximum oxygen uptake. The findings from treadmill running studies at varying intensities and durations in C57BL/6J mice revealed that treadmill running improved hippocampal neurogenesis and memory in wild-type (WT) mice in an intensity-dependent manner. Omics and UK Biobank cohort analyses identified muscle-derived CTSB as a key exercise-responsive factor, whose expression may be regulated by O-linked <i>N</i>-acetylglucosaminylation. Overexpression of O-linked <i>N</i>-acetylglucosaminyltransferase (OGT) prolonged the half-life of CTSB and inhibited its ubiquitination-mediated degradation, whereas inhibition of OGT accelerated its degradation. Mechanistically, treadmill running may promote the secretion of muscle-derived CTSB into the bloodstream via EVs and its subsequent delivery to the hippocampus through activation of the OGT/CTSB signaling. In WT mice, knockdown of muscular CTSB partially reversed the treadmill-running-induced improvements in hippocampal neurogenesis and memory, while overexpression of muscular OGT further enhanced the release of muscle-derived CTSB. Moreover, in amyloid precursor protein/presenilin 1 mice, treadmill running potentially improved cognitive function, reduced amyloid-β deposition, neurofibrillary degeneration, and neuroinflammation by up-regulating muscular CTSB. Knockdown of muscular CTSB attenuated the benefits of treadmill running, while overexpression of CTSB further enhanced the exercise-induced effects. Overall, this study demonstrates that treadmill running may activate the muscular OGT/CTSB signaling axis, promoting the secretion of the myokine CTSB protein into the circulatory system via EVs and its transport to the brain, thereby improving hippocampal neurogenesis and cognitive function in both WT and amyloid precursor protein/presenilin 1 mice. These findings highlight the role of myokine CTSB as a pivotal modulator in muscle-brain axis communication mechanism, with its stability regulated by O-linked <i>N</i>-acetylglucosaminylation.</p>","PeriodicalId":21120,"journal":{"name":"Research","volume":"9 ","pages":"1233"},"PeriodicalIF":10.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}