Journal of Translational Medicine最新文献

{"title":"Bio fluid exosomes: promises, challenges, and future directions in translational medicine.","authors":"Fatemeh Soltanmohammadi, Maryam Maghsoodi, Effat Alizadeh, Khosro Adibkia, Yadollah Azarmi, Adel Mahmoudi Gharehbaba, Yousef Javadzadeh","doi":"10.1186/s12967-025-06886-5","DOIUrl":"10.1186/s12967-025-06886-5","url":null,"abstract":"<p><p>Exosomes, a subset of extracellular vesicles (EVs) secreted by virtually all cell types, have emerged as pivotal nanocarriers of bioactive molecules, including proteins, nucleic acids, and lipids, facilitating intercellular communication and modulating physiological and pathological processes. Initially discovered in reticulocytes, exosomes have since been recognized for their diverse roles in immune regulation, antigen presentation, and disease progression, paving the way for their application in diagnostics, therapeutics, and personalized medicine. This review comprehensively examines biofluid-derived exosomes, focusing on their biogenesis, molecular composition, and innovative isolation techniques from various biological fluids. We highlight their diagnostic potential as non-invasive biomarkers for diseases such as cancer, neurodegenerative disorders, and infectious diseases, as well as their therapeutic applications in drug delivery, regenerative medicine, and immunotherapy. Additionally, we discuss ongoing and completed clinical trials leveraging exosomes for precision medicine, while addressing the technical challenges and limitations in exosome isolation, characterization, and clinical translation. By integrating the latest advancements and future perspectives, this review underscores the transformative potential of biofluid exosomes in revolutionizing modern medicine.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"993"},"PeriodicalIF":7.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131106","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":"Facilitating consumer partnerships in health research.","authors":"Raluca Ghebosu, Leonie Young, Benedette Watson, Merran Williams, Ashley Dedmon, Jo Maxwell, Erik W Thompson, Fernando Souza-Fonseca-Guimaraes, Joy Wolfram","doi":"10.1186/s12967-025-07035-8","DOIUrl":"10.1186/s12967-025-07035-8","url":null,"abstract":"<p><strong>Background: </strong>Consumer engagement and involvement in health research is a well-established and growing priority for a better-informed public, a broader voice for research in relation to impact and funding, and guidance toward issues that matter most to consumers. These well recognized benefits of consumer engagement in research can be strengthened through training.</p><p><strong>Methods: </strong>We describe a workshop for health researchers and consumers that was designed to provide a networking opportunity and introductory training, drawing from experience in Australia and the United States. Participants completed pre- and post-workshop surveys to assess the impact of the workshop.</p><p><strong>Results: </strong>The workshop led to enhanced consumer awareness of contributions that can be made to all stages of the research cycle. Researchers who participated in the workshop had improved confidence and understanding of how to build partnerships with consumers. The development of sustainable financial models to provide ongoing training opportunities for consumers and researchers was identified as a critical priority. The workshop also led to the establishment of a new model that classifies consumer contributions to research into three tiers, based on varying levels of time commitment, training, scientific understanding, and managerial skills.</p><p><strong>Conclusion: </strong>The workshop was well received as a networking and training opportunity, complementing other training frameworks for consumers and researchers. Training, funding, and supportive institutional policies were identified as key enablers for effective collaboration between consumers and researchers.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"990"},"PeriodicalIF":7.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113662","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":"A novel bispecific affitoxin simultaneously targeting E7 of HPV16/18 types: superior anti-tumor activity and EMT reversal in HPV-driven cervical cancer therapy.","authors":"Kairong Wan, Lijun Yu, Sicong Feng, Zhenyun Xie, Yanheng Li, Xisha Jing, Junze Wu, Lifang Zhang, Wenshu Li","doi":"10.1186/s12967-025-06971-9","DOIUrl":"10.1186/s12967-025-06971-9","url":null,"abstract":"<p><strong>Background: </strong>Sustained infection with high-risk HPV of the 16 and 18 types is accounted for nearly 75% of cervical cancer (CC), but now there is an absence of agents aimed at eradicating HPV infections. Notwithstanding, affibody-based affitoxins may represent a breakthrough in tumor-targeted therapy. Our previous work has constructed a bispecific affibody simultaneously targeting the early oncogenic proteins E7 of HPV16 and 18 types (named as Z_HPV16-18E7). In the present study, Granzyme B (GrB, cytotoxic effector) was introduced to construct three bispecific affitoxins for the enhanced therapy against HPV-infected CC cells.</p><p><strong>Methods: </strong>Three forms of the affitoxin constructs (GrB-Z_HPV16-18E7, Z_HPV16E7-GrB-Z_HPV18E7, and Z_HPV16-18E7-GrB) were designed and prepared, and their binding to the target protein and cells were confirmed by SPR analysis and a confocal immunofluorescence assay. The inhibition of cell viability by a CellTiter-Lumi™ luminescence assay, the induction of apoptosis by a fluorometric TUNEL method, and the reversal of EMT by wound healing and transwell assays, for the affitoxins against the target cells were evaluated. The in vivo inhibition in tumor-bearing mice along with the acute toxicity, pharmacokinetics, and stability of the affitoxins were tested.</p><p><strong>Results: </strong>Two bispecific affitoxins of Z_HPV16E7-GrB-Z_HPV18E7 and Z_HPV16-18E7-GrB were successfully prepared. They can bind to the target protein and cells, inhibited cell viability as well. Compared to the bispecific affibody (without GrB), the bispecific affitoxins induced a more pronounced apoptosis characterized by the release of active caspase-3 and may inhibit cell migration by reversing the epithelial-mesenchymal transition (EMT) pathway. In vivo, the bispecific affitoxin exhibited significant tumor-targeting accumulation in tumor-bearing mice. Compared to the bispecific affibody, the bispecific affitoxin showed a more significant inhibition of the growth of the xenograft tumor in mice, with no acute toxic reactions and a certain degree of stability.</p><p><strong>Conclusions: </strong>This work has developed a bispecific affitoxin that simultaneously targets HPV16- and HPV18-type CC cells, with a significant dual-functional advantage, combining the targeted inhibitory of the affibody with the cytotoxicity of the toxin molecule. Our research offers a novel design and approach for targeted therapy in HPV-driven cervical cancer.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"992"},"PeriodicalIF":7.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124988","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":"Gut microbiota dysbiosis and systemic immune dysfunction in critical ill patients with multidrug-resistant bacterial colonization and infection.","authors":"Zongxin Ling, Wenwen Ding, Xia Liu, Jingchen Zhang, Yiwen Cheng, Zhangcheng Zhu, Lingbin Wu, Xiaocui Xu, Yongtao Gao, Ruilai Jiang","doi":"10.1186/s12967-025-07049-2","DOIUrl":"10.1186/s12967-025-07049-2","url":null,"abstract":"<p><strong>Background: </strong>Antimicrobial resistance (AMR) poses a global health threat, particularly in critically ill patients with multidrug-resistant organism (MDRO) colonization or infection. While evidence suggests the gut microbiota plays a critical role in MDRO colonization and infection, its specific characteristics and the host immune response remain poorly understood.</p><p><strong>Methods and results: </strong>This case-control study compared 88 MDRO-infected patients, 100 MDRO-colonized patients, and 86 healthy controls, using 16S rRNA sequencing and cytokine profiling. MDRO cohorts exhibited profound gut dysbiosis, including reduced gut microbial diversity and distinct community structures, reduced beneficial bacteria (e.g., Bacteroides, Faecalibacterium, Roseburia, Prevotella), and expansion of pathobionts-resident microbes with pathogenic potential (e.g., Enterococcus, Klebsiella, Escherichia-Shigella). Enterotype analysis revealed a shift from a Bacteroides-dominated to one Enterococcus-dominated microbiota in both colonized and infected patients compared to controls. Serum cytokine profiling indicated immune dysfunction in MDRO-associated patients. Correlation analysis showed that beneficial genera were negatively correlated with pro-inflammatory cytokines (IL-1ra, IL-2, IL-7, TNF-α, and IFN-γ) and positively associated with anti-inflammatory markers, while pathobionts exhibited the opposite trend. Several key differential genera, such as Enterococcus and Klebsiella, either individually or in combination, have been identified as key discriminators of MDRO status. Functional predictions through PiCRUSt observed disruptions in carbohydrate and lipid metabolism in the MDRO cohorts.</p><p><strong>Conclusion: </strong>Overall, MDRO colonization and infection lead to gut dysbiosis and immune dysfunction, with microbiota-immune interactions playing a crucial role in disease progression, suggesting the gut microbiota as a potential diagnostic and therapeutic target for AMR.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"981"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959064","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":"Comments on \"heavy metals and their relationships with lung function and airway inflammation: insights from a population-based study\".","authors":"Tao Luo, Tao Chen","doi":"10.1186/s12967-025-06999-x","DOIUrl":"10.1186/s12967-025-06999-x","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"977"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959063","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":"Validated methods for isolation and qualification of mesenchymal stromal/stem cells from different sources.","authors":"Vincenzo Mattei, Francesca Santilli, Fanny Pulcini, Jessica Fabrizi, Loreto Lancia, Costantino Santacroce, Francesca Megiorni, Simona Ceccarelli, Emanuela Paldino, Roberto Gramignoli, Maria G Roubelakis, Sadri Bahareh, Massoud Vosough, Sveva Bollini, Umberto Galderisi, Antonio Jose Salgado, Antonio Angeloni, Cinzia Marchese, Simona Delle Monache","doi":"10.1186/s12967-025-06972-8","DOIUrl":"10.1186/s12967-025-06972-8","url":null,"abstract":"<p><p>Mesenchymal Stromal/Stem Cells (MSCs) have attracted considerable attention in the field of regenerative medicine. Their unique properties make them suitable for various therapeutic applications. This article reviews accepted methods and guidelines for the isolation and characterization of MSCs from various sources. Common sources include bone marrow, adipose tissue, perinatal and umbilical cord tissue, dental pulp, etc. Naturally, the techniques used to isolate MSCs can vary depending on the source from which they are derived. However, several methods have been widely accepted by the scientific community. These include enzymatic digestion, density gradient centrifugation, the use of Percoll, adherence-based techniques and selective culture conditions. To characterize MSCs, basic criteria established by the International Society for Cell and Tissue Transplantation and the International Federation for Adipose Tissue are routinely used. These criteria include the ability of MSCs to adhere to plastic surfaces under standard culture conditions, the expression of specific membrane markers and their differentiation potential. Various techniques are used to assess these characteristics, including mixed lymphocyte reactions, flow cytometry and immunophenotyping profiles. These assessments aim to confirm the purity of the MSCs and validate their mesenchymal properties. In summary, the isolation and characterization of MSCs requires careful consideration of the different available methods. Each source presents unique challenges and advantages. By following established guidelines, researchers can ensure successful isolation and characterization of MSCs. This knowledge will ultimately improve their use in regenerative medicine.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"975"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959058","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":"Inflammatory mitochondrial signalling and viral mimicry in cancer.","authors":"Salvatore Nesci, Saverio Marchi, Joyce Hu, Francesco M Marincola, Cristina Algieri","doi":"10.1186/s12967-025-06931-3","DOIUrl":"10.1186/s12967-025-06931-3","url":null,"abstract":"<p><p>Endogenous transposable elements (TEs) are receiving increasing attention as potential targets to develop novel immunostimulatory strategies against cancer. Indeed, the defective epigenetic suppression of TEs in malignant cells offers a therapeutic window to enable their re-activation with at least some degree of selectivity. In line with this notion, multiple clinically employed epigenetic modifiers such as DNA-demethylating agents have been shown to promote the re-expression of TEs in preclinical tumour models, hence driving powerful inflammatory responses that enables increased sensitivity of immunitary immune cells to immunotherapy with immune checkpoint inhibitors (ICIs). This phenomenon is commonly referred to as \"viral mimicry\" as (at least in part) it impinges on the activation of immunological pathways commonly driven by viral infection, notably the detection of cytosolic nucleic acids by pattern recognition receptors. Here, we critically discuss the molecular mechanisms through which the mitochondria-dependent cGAS-STING and MAVS pathways enable viral mimicry as elicited by the re-activation of TEs in neoplastic cells, as we comment on the therapeutic potential of using epigenetic modifiers to harness these mechanisms in support of restored ICIs sensitivity across cancer types.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"982"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958750","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":"Multi-task machine learning for transfusion decision support in acute upper gastrointestinal bleeding: a novel ensemble approach with clinical validation.","authors":"Qiongjie Li, Guolin Chen, Qun Li","doi":"10.1186/s12967-025-06995-1","DOIUrl":"10.1186/s12967-025-06995-1","url":null,"abstract":"<p><strong>Background: </strong>This study proposes a multi-task learning (MTL) model to predict the need for blood transfusion in patients with acute upper gastrointestinal bleeding (AUGIB), as well as to estimate the appropriate type and volume of transfusion. The proposed model demonstrates improved predictive performance over existing scoring systems and aims to support clinical decision-making in transfusion management.</p><p><strong>Methods: </strong>Clinical data were retrospectively collected from 1256 emergency patients with AUGIB admitted to the First Hospital of Shanxi Medical University from January 1, 2022, to December 31, 2023. An external validation cohort (n = 209) was sourced from Fenyang Hospital, Shanxi Province, using identical inclusion criteria. The MTL model integrates oversampling techniques and distribution correction to address data imbalance. A soft-voting ensemble of CatBoost and XGBoost classifiers was used for the classification task, while a stacked regressor combining random forest and XGBoost was employed for the regression task. Model performance was further optimized through a dynamically weighted loss function.</p><p><strong>Results: </strong>In the classification task, the model achieved an area under the curve (AUC) of 0.965, representing a 20.5% improvement over the traditional Glasgow-Blatchford Score (GBS). In the regression task, the two-stage stacked regressor (TSR) outperformed other machine learning models in predicting transfusion type and volume , significantly reducing the prediction error of transfusion volume. Compared to random forest (RF), XGBoost, multilayer perceptron (MLP), and backpropagation neural network (BP), the model reduced the overall loss by 9.9%, 21.0%, 38.3%, and 10.0%, respectively, validating the advantages of hierarchical feature selection and dynamic task-weighting. In the external validation set, the model exhibited favorable generalization performance with an AUC of 0.860, and showed good performance in infusion volume prediction error and weighted loss CONCLUSIONS: This study presents a robust and interpretable multi-task learning model for transfusion decision-making in AUGIB. By jointly optimizing classification and regression tasks through hierarchical feature selection and dynamic loss allocation, the model supports precision transfusion strategies and holds strong potential for broader application in emergency and critical care settings.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"979"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958884","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":"Establishing next-generation reference intervals for pro-gastrin-releasing peptide using a dynamic modeling approach.","authors":"Dong Zhu, Haibin Zhao, Weicheng Zhang, Xiuying Zhao","doi":"10.1186/s12967-025-07014-z","DOIUrl":"10.1186/s12967-025-07014-z","url":null,"abstract":"<p><strong>Background: </strong>Serum pro-gastrin-releasing peptide (ProGRP) levels significantly vary with age. However, conventional partitioned reference intervals (RIs) fail to reflect the continuous and subtle physiological changes associated with aging. To address this limitation, we investigated the age- and sex-specific dynamics of ProGRP levels and innovatively developed next-generation RIs for adults and elderly individuals in North China.</p><p><strong>Methods: </strong>A total of 4136 rigorously screened individuals (aged 20-80 years) were analyzed. The effects of age and sex on ProGRP levels were assessed using Mann-Whitney U tests, Spearman's correlation, and Kruskal-Wallis tests. The Harris-Boyd method was used to evaluate the necessity of sex or age partitioning. Age-partitioned RIs were established using a nonparametric method. Next-generation RI models were developed using generalized additive models for location, scale, and shape, with age-related dynamics visualized. The clinical applicability of both RI types was evaluated by comparing upper reference limit flagging rates across age subgroups; rates closer to the theoretical 2.5% were considered indicative of superior RI accuracy.</p><p><strong>Results: </strong>Sex had a minimal and clinically insignificant effect on ProGRP levels. In contrast, age had a significant effect: concentrations remained stable until approximately 40 years of age, followed by progressive increases. The partitioned RIs were defined as 0-52.77 pg/mL (20-49 years) and 0-63.68 pg/mL (≥ 50 years). Next-generation RIs were quantified and visualized. Compared with partitioned RIs, next-generation RIs yielded reference limit flagging rates more closely aligned with the theoretical 2.5% across most age groups and demonstrated significantly greater stability (1.83%-3.74% vs. 1.07%-7.10%).</p><p><strong>Conclusions: </strong>Compared with partitioned RIs, next-generation RIs for ProGRP improve the accuracy of laboratory result interpretation. With advances in laboratory informatics, broader clinical implementation of next-generation RIs is anticipated.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"983"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959047","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":"The circRNA-mediated ceRNA molecular regulatory network in fatigue-type type 2 diabete.","authors":"Xian-Jie Zhen, Tao Wu, Min Zhang, Chu-Yue Zhang, Rui-Jie Liu, Jing Jiang, Guang-Jian Jiang","doi":"10.1186/s12967-025-07007-y","DOIUrl":"10.1186/s12967-025-07007-y","url":null,"abstract":"<p><p>Fatigue is a common but poorly understood issue in type 2 diabetes (T2DM) that affects quality of life. Although ceRNA networks regulate disease progression, their role in T2DM-related fatigue (F-T2DM) is unclear. This study developed a circRNA-mediated ceRNA network to uncover the molecular interactions causing fatigue in F-T2DM. The study included healthy control group (Control, n = 21), F-T2DM group (n = 21), and non-fatigue type 2 diabetes patients (NF-T2DM, n = 21). By combining high-throughput sequencing to screen differentially expressed circRNAs (F-T2DM vs Control: 1144; F-T2DM vs NF-T2DM: 1303) and mRNAs (F-T2DM vs Control: 912; F-T2DM vs NF-T2DM: 1190), it was found that hsa_circ_0078539 and hsa_circ_0026239 were significantly upregulated in F-T2DM compared to both Control and NF-T2DM groups, and their host genes were involved in cytoskeleton remodeling. The GO/KEGG enrichment analysis combined with weighted gene co-expression network (WGCNA) of F-T2DM compared with Control indicated that the core pathways of F-T2DM focused on actin cytoskeleton dynamic regulation, AMPK signaling pathway, tricarboxylic acid cycle, and oxidative stress response. In the enrichment analysis of F-T2DM and NF-T2DM, cytoskeleton dynamics regulation, AMPK signaling pathway, and tricarboxylic acid cycle were further enriched, and the specific activation of reactive oxygen metabolism balance and AGE-RAGE pathway was also observed. Further, through multi-database prediction and experimental verification, a F-T2DM-specific ceRNA network was constructed, and key regulatory axes hsa_circ_0044623/hsa-mir-129-5p/MYLK3, hsa_circ_0002622/hsa-mir-200b-3p/RAB21, and hsa_circ_0078539/hsa-mir-4695-3p/SLC7A14 were screened out. The ceRNA regulatory network in human and animal samples was confirmed using RT-qPCR. These axes drive the pathological process by regulating myocardial contractility efficiency, glucose transport, mitochondrial energy metabolism, and insulin signaling pathway. This study clarified the molecular regulatory mode of patients with fatigue type 2 diabetes from the perspective of ceRNA network, providing a new direction for the research on diabetes classification and diagnosis.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"973"},"PeriodicalIF":7.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959029","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}