Journal of Translational Medicine最新文献

{"title":"Synbiotics in Alzheimer's disease: mechanisms, clinical evidence, and therapeutic prospects.","authors":"Yuhua Lin, Rongping Weng, Huayang Pan, Yangbo Hou, Yipeng Sun, Junkai Wen","doi":"10.1186/s12967-025-07064-3","DOIUrl":"10.1186/s12967-025-07064-3","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence implicates gut microbiota (GM) dysbiosis in Alzheimer's disease (AD) pathogenesis via the gut-brain axis. Dysbiosis contributes to neuroinflammation, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier disruption, and cognitive decline. Synbiotics (combinations of probiotics and prebiotics) offer a promising strategy to modulate GM, potentially ameliorating these AD hallmarks through multiple mechanisms including enhanced production of neuroprotective short-chain fatty acids (SCFAs), reduced inflammation, improved gut barrier integrity, and immunomodulation.</p><p><strong>Objective: </strong>This review critically evaluates the current evidence on the therapeutic potential of synbiotics for AD. It aims to synthesize findings from preclinical and clinical studies regarding the efficacy of synbiotics in improving cognitive function and AD pathology, elucidate the underlying biological mechanisms including GM modulation, SCFA production, immune regulation, and gut-brain signaling, and identify key challenges and future research directions for translating GM-targeted interventions into effective AD therapies.</p><p><strong>Conclusion: </strong>Synbiotics demonstrate significant potential, particularly in early AD, by improving cognitive domains, reducing neuroinflammation and AD biomarkers, and modulating beneficial microbial metabolites. However, challenges include confounding factors, unresolved questions about causality, inconsistent results in advanced disease, and insufficient large-scale human trials. Future success hinges on rigorous longitudinal randomized controlled trials integrating multi-omics approaches, advanced in vitro models, and personalized strategies considering baseline microbiota and host genetics. While not a standalone cure, synbiotics represent a valuable component within multi-target therapeutic approaches aimed at modulating the gut-brain axis to slow AD progression.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1009"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the prevention gap: funding distribution and methodological shifts in prevention-focused biomedical research under EU framework programmes.","authors":"Francesca Pistollato, Fabia Furtmann, Annalisa Gastaldello, Roberta Pastorino, Eleni Petra, Ignacio J Tripodi, Helder Constantino","doi":"10.1186/s12967-025-07019-8","DOIUrl":"10.1186/s12967-025-07019-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Noncommunicable diseases (NCDs) contribute significantly to global morbidity and mortality, accounting for 74% of all deaths worldwide. Many of these chronic diseases can be prevented or their onset mitigated through lifestyle interventions. Complementing these efforts, robust biomarkers enable early diagnosis (secondary prevention), while tertiary prevention can reduce long-term complications and improve disease management. Moreover, the importance of prevention extends beyond NCDs to infectious diseases, where lifestyle-related factors can also play a pivotal role. Innovative human-based research methods have shown suitable for modeling several diseases and advancing drug discovery. These approaches are particularly relevant in prevention research, given the inherently human nature of the lifestyle and environmental factors associated with disease risk and progression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Here we conducted a retrospective evaluation of biomedical research projects funded under the 7th Framework Programme (FP7), Horizon 2020, and currently ongoing Horizon Europe (HE). We developed and refined a computer-based approach based on the use of Natural Language Processing (NLP) to examine three key aspects: (i) the integration of primary, secondary, and tertiary prevention in these projects, (ii) the biomedical research areas which most frequently incorporate prevention, and (iii) the use of animal-based research versus human-centric approaches.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our findings reveal a persistent gap in the percentage of prevention-focused biomedical research projects, with only 4.4%, 4.5%, and 1.9% of FP7, H2020, and HE projects, respectively, addressing prevention. This gap was particularly pronounced in certain biomedical research areas, such as age-related diseases and diabetes and metabolic syndrome research, which showed a decrease in the percentage of prevention-related projects especially under most recent framework programme (HE). While the reliance on animal-based methods has been generally modest, averaging around 26% of all prevention-related projects, tertiary prevention research, and prevention projects focused on some biomedical areas (i.e., age-related diseases, personalized medicine, antimicrobial resistance, bone disorders, and respiratory diseases) showed increased percentages in projects using animals under more recent FPs. Analysis of funding distribution revealed progressively less funding allocated to prevention-related projects focused on diabetes and metabolic syndrome, neurodegenerative diseases, age-related disorders, and AMR. In addition, the proportion of funding allocated to both secondary and tertiary prevention decreased under HE.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;A shift toward human-centric approaches, particularly in prevention-focused research, is essential to enhance the translatability of findings. As policymakers prepare for the next EU funding framework, ","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1006"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolutionizing Wilson disease prognosis: a machine learning approach to predict acute-on-chronic liver failure.","authors":"Zhihong Rao, Wenming Yang, Yulong Yang, Yue Yang, Yongsheng Han, Xiang Li, Siyang Lu, Yuchen Li, Hu Xi, Ke Diao, Shuzhen Fang, Wei He, Sihuan Zhu","doi":"10.1186/s12967-025-06987-1","DOIUrl":"10.1186/s12967-025-06987-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Wilson disease (WD), an inherited copper metabolism disorder, is a cause of acute-on-chronic liver failure (ACLF), posing life-threatening risks due to rapid progression. This study aimed to develop a machine learning (ML)-based model to predict ACLF risk in WD patients.</p><p><strong>Methods: </strong>We retrospectively analyzed 3692 WD patients (Leipzig score ≥ 4) from The First Affiliated Hospital of Anhui University of Chinese Medicine (2014-2024), including 104 ACLF and 104 non-ACLF cases. The original data set was randomly divided into the training and test cohorts in a ratio of 7:3. Demographic, biochemical, and ultrasound data were collected. Six ML algorithms (LR, SVM, KNN, ExtraTrees, XGBoost, LightGBM) were applied to construct a predictive model, with SHAP explaining feature importance.</p><p><strong>Results: </strong>The XGBoost model achieved optimal performance (AUC: 0.998, accuracy: 0.968). Key predictors included TBA, APTT, diagnosis age, onset age, Hb. Elevated TBA, APTT and diagnosis age correlated with higher ACLF risk, while reduced onset age and Hb indicated poorer outcomes. Additional parameters (TT, Cl^-, CER and hepatic imaging features) also contributed modestly to predictions.</p><p><strong>Conclusions: </strong>The ML-based model effectively predicts WD-ACLF risk, with XGBoost demonstrating superior performance. TBA, APTT, diagnosis age, onset age and Hb emerged as critical biomarkers, offering actionable insights for early clinical intervention.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"999"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human genetic variations conferring resistance to malaria.","authors":"Xiaokun Zhang, Jie Wu, Yunxing Peng, Lan Luo, Lu Zhang, Xi Huang, Guoying Chen, Yirong Li, Haoan Yi","doi":"10.1186/s12967-025-07017-w","DOIUrl":"10.1186/s12967-025-07017-w","url":null,"abstract":"<p><p>Malaria remains one of the most significant public health challenges globally, particularly in tropical and subtropical regions. Throughout evolutionary history, malaria-induced natural selection has profoundly influenced human genetic evolution, leading to the emergence of numerous genetic variations that confer resistance to the disease. These adaptations highlight the complicated interplay between pathogens and human genetics. This review focuses on key genetic variations associated with malaria resistance, including hemoglobinopathies (such as sickle cell trait and thalassemia), glucose-6-phosphate dehydrogenase deficiency, blood group polymorphisms and genetic variants related to inflammation and immune regulation. The prevalence of these genetic adaptations varies widely across different geographic regions, reflecting the historical burden of malaria in those areas. Despite significant advancements in genetic research, the precise mechanisms by which these mutations confer protection against malaria remain incompletely understood. Furthermore, the interactions between these genetic factors and environmental influences add to another layer of complexity. A comprehensive understanding of these genetic variations and their functional implications is crucial for advancing malaria epidemiology, improving diagnostic tools, and developing targeted prevention and control strategies, ultimately contributing to global efforts to eradicate malaria.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"997"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In reference to \"VEGF secreted by human dental pulp stem cell promotes spinal cord injury repair by inhibiting microglial pyroptosis through the PI3K/AKT pathway\".","authors":"Cheng Xue","doi":"10.1186/s12967-025-06536-w","DOIUrl":"10.1186/s12967-025-06536-w","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"994"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive models for live birth outcomes following fresh embryo transfer in assisted reproductive technologies using machine learning.","authors":"Shengnan Wu, Xinbo Wang, Yuechen Liu, Yongyong Ren, Mei Zhao, Haitao Song, Hao Shen, Yueting Wu, Zhiyun Wei, Hui Lu, Kunming Li","doi":"10.1186/s12967-025-07045-6","DOIUrl":"10.1186/s12967-025-07045-6","url":null,"abstract":"<p><strong>Background: </strong>Infertility affects approximately 15% of couples globally, with assisted reproductive technologies (ARTs) becoming the primary interventions. Despite the growing use of ARTs, success rates have plateaued at around 30%, highlighting the need for improved predictive models to enhance outcomes. This study aimed to develop a machine learning-based predictive model for live birth outcomes following fresh embryo transfer.</p><p><strong>Methods: </strong>A total of 51,047 ART records were collected from 2016 to 2023 at the Shanghai First Maternity and Infant Hospital. After data preprocessing, 11,728 records and 55 pre-pregnancy features were analyzed. Six machine learning models-Random Forest (RF), eXtreme Gradient Boosting (XGBoost), Gradient Boosting Machines (GBM), Adaptive Boosting (AdaBoost), Light Gradient Boosting Machine (LightGBM), and Artificial Neural Network (ANN)-were employed to construct the prediction model.</p><p><strong>Results: </strong>Among the models, RF demonstrated the best predictive performance, achieving an area under the curve (AUC) value exceeding 0.8. Key predictive features included female age, grades of transferred embryos, number of usable embryos, and endometrial thickness. A web tool was developed to assist clinicians in predicting outcomes and individualizing treatments based on patient data.</p><p><strong>Conclusions: </strong>This study presents a significant advancement in predicting live birth outcomes prior to embryo transfer, moving beyond traditional assessments. The findings underscore the potential of machine learning to improve clinical decision-making and enhance patient counseling in ARTs.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1004"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microenvironmental determinants of cancer progression during obesity: emerging evidence and novel perspectives.","authors":"Rossella Salemi, Valentina Sergi, Maria Sofia Basile, Sara Bravaccini, Lucia Frittitta, Adriana Carol Eleonora Graziano, Agnese Filippello, Roberta Malaguarnera, Ernestina Marianna De Francesco","doi":"10.1186/s12967-025-06970-w","DOIUrl":"10.1186/s12967-025-06970-w","url":null,"abstract":"<p><p>Obesity is a global pandemic representing a significant public health threat, with a rising number of affected individuals and numerous associated co-morbidities, including cancer. In obese cancer patients, higher mortality rates are usually observed compared to normal weight/lean individuals. The imbalanced metabolic asset of obese patients fosters tumor growth and its progression by impacting not only on cancer cells, but also affecting their cross-talk with the tumor microenvironment, which represents a relevant and multifaceted player in disease progression. Herein, we deliver a detailed overview of certain peculiar players implicated in the reprogramming of the tumor microenvironment during obesity toward disease evolution. We highlight the key metabolic, molecular and cellular players that co-opt cancer cells and their microenvironment to foster disease progression. We emphasize the role of certain hormones and growth factors-dependent pathways (Insulin/IGF signaling system and VEGF/VEGFR axis) together with inflammatory pathways (RAGE signaling system) in triggering microenvironmental-dependent evolution of neoplastic disease during obesity. Finally, we underline current pitfalls and envisage innovative tools and future directions for better investigating tumor progression in obesity.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"995"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-driven inflammation: a new frontier in ovarian ageing.","authors":"Wenhan Ju, Binghan Yan, Danping Li, Fang Lian, Shan Xiang","doi":"10.1186/s12967-025-06966-6","DOIUrl":"10.1186/s12967-025-06966-6","url":null,"abstract":"<p><p>Ovarian ageing is a key factor in the decline of female fertility. It is primarily characterised by diminished oocyte quality, follicular depletion, and dysregulated hormone levels. In recent years, mitochondria-driven inflammation has emerged as a potential mechanism in ovarian ageing. Mitochondrial dysfunction results in the accumulation of reactive oxygen species (ROS) and the release of mitochondrial DNA (mtDNA), as well as the leakage of mitochondrial components and metabolites into the cytosol or extracellular space. These elements act as damage-associated molecular patterns (DAMPs), activating inflammasomes like NLRP3, thereby initiating and amplifying innate immune responses and contributing to sustained inflammation. Furthermore, an imbalance in mitochondrial quality control mechanisms can worsen the spread and persistence of inflammatory responses. In this study, we present a comprehensive overview of the signalling origins, molecular mechanisms of amplification, and key regulatory nodes involved in mitochondria-driven inflammation during ovarian ageing. Finally, we summarise potential therapeutic strategies targeting mitochondria-driven inflammation, offering novel perspectives and targets for delaying ovarian ageing and enhancing female reproductive health.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1005"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia reverses the early anti-inflammatory microglial response to the β-amyloid peptide: mitochondrial involvement and beneficial roles of melatonin and naringenin.","authors":"Cristiana Lucia Rita Lipari, Aurora Patti, Stefano Conti-Nibali, Angela Anna Messina, Andrea Magrì, Maria Angela Sortino, Sara Merlo","doi":"10.1186/s12967-025-07044-7","DOIUrl":"10.1186/s12967-025-07044-7","url":null,"abstract":"<p><strong>Background: </strong>Early Alzheimer's disease (AD) is characterized by anti-inflammatory microglial responses to the beta amyloid peptide (Aβ), which later switch to pro-inflammatory. Such transition is relevant to disease progression and can be affected by concurrent insults, such as hypoxia (HY). This study explored whether a mild hypoxic stimulus could anticipate the microglial phenotypic switch, focusing in particular on involvement of SIRT1 and mitochondrial function.</p><p><strong>Methods: </strong>HMC3 human microglia were polarized to an anti-inflammatory phenotype by 3 h of exposure to 0.2 μM of Aβ42 to mimic early AD and transferred to a hypoxic chamber with 3% of O₂ for 1 h. Effects on microglial activation were investigated by analysis of the SIRT1-BDNF axis activation and enzymatic and ELISA assays of inflammatory markers. Mitochondrial function and morphology were analyzed by high resolution respirometry and laser scanning confocal microscopy.</p><p><strong>Results: </strong>Hypoxia (HY) prevented the Aβ42-induced early induction of SIRT1 translocation and BDNF release and significantly increased caspase 1 and NF-kB activity. Moreover, mitochondrial oxygen flows evaluated by high resolution respirometry were significantly reduced, while mitochondrial area, perimeter and branching were increased by Aβ42 + HY, compared to Aβ alone. These changes were contrasted by both melatonin (1 μM) and naringenin (10 μM), natural substances able to induce SIRT1. However, use of the selective SIRT1 inhibitor EX-527 (5 μM) suggested only a partial involvement for SIRT1 in the observed effects, prevalent for naringenin.</p><p><strong>Conclusions: </strong>Our results suggest that mild hypoxic insults during early asymptomatic stages of AD can pose as a risk factor for an accelerated progression of the disease and show the benefits of SIRT1 induction strategies, including use of natural substances like melatonin and naringenin.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1012"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triclabendazole inhibits PKM2 nuclear localization and glycolysis by enhancing HDAC6-mediated deacetylation in lung cancer.","authors":"Liang Yan, Yong Sun, Shan-Shan Shi, Yuan Li, Yi-Fan Zhang, Liang-Zhuo Qu, Jing Liu, Yong Dai, Qing-Bing Zha, Jun Fan","doi":"10.1186/s12967-025-06905-5","DOIUrl":"10.1186/s12967-025-06905-5","url":null,"abstract":"<p><strong>Background: </strong>Metabolic reprogramming is a hallmark of cancer cells, enabling them to meet the heightened energetic and biosynthetic demands required for rapid growth and proliferation. Recently, non-canonical functions of metabolic enzymes have garnered significant attention in cancer research. Pyruvate kinase 2 (PKM2) has been identified as a key player in transcriptional regulation within the nucleus, presenting new opportunities for therapeutic interventions in cancer.</p><p><strong>Methods: </strong>In this study, the cells (A549 and H1299) were treated with indicator concentration of triclabendazole. The effects of triclabendazole on proliferation was detected by CCK8 assay, colony formation assay, EdU staining, and cell count assay. A tumorigenesis study in nude mice was performed to demonstrate the inhibitory effect of triclabendazole on tumor growth. PKM2 nuclear translocation, HDAC6-mediated deacetylation, glycolytic flux downregulation, and activation of AMPK/mTOR signaling pathway were used to elucidate the mechanistic role of triclabendazole in lung cancer progression.</p><p><strong>Results: </strong>This study discovered that triclabendazole, a novel benzimidazole derivative, commonly used against Fasciola hepatolithiasis, effectively inhibited the nuclear translocation of PKM2. This inhibition resulted in the downregulation of glycolytic flux, ultimately suppressing lung cancer cell proliferation. Notably, triclabendazole reduced PKM2 acetylation by promoting the interaction between PKM2 and histone deacetylase 6 (HDAC6), thus blocking PKM2 nuclear localization. Moreover, we also demonstrated that triclabendazole-mediated inhibition of cell proliferation is driven by the downregulation of glycolysis, which enhanced AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling. Consistently, triclabendazole administration significantly inhibited tumor growth in vivo, correlating with the blockade of PKM2 nuclear translocation and lactate production decreased.</p><p><strong>Conclusion: </strong>Our findings revealed that triclabendazole inhibits PKM2 nuclear localization and glycolysis through an HDAC6-dependent mechanism, leading to the activation of AMPK/mTOR signaling and suppression of lung cancer cell proliferation. These results suggested that triclabendazole holds promise as a potential therapeutic agent, with the HDAC6-PKM2 axis representing a novel target for lung cancer treatment.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"1001"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}