Military Medical Research最新文献

{"title":"Advanced multifunctional nano-delivery platform focusing on treating diseases related to lipid metabolism via targeted intervention in various lipid metabolic processes.","authors":"Ying Sun, Kai Yan, Yi Zhang, Yan-Qi Han, Long-Hui Hao, Yue Gao, Hong-Liang Wang, Hong-Qian Chu, Jun Ye, Yu-Ling Liu, Yan-Fang Yang","doi":"10.1186/s40779-025-00672-6","DOIUrl":"10.1186/s40779-025-00672-6","url":null,"abstract":"<p><p>Disruptions in lipid metabolism cause numerous metabolic diseases, including obesity, diabetes, cardiovascular diseases, and liver disorders. Consequently, lipid metabolism serves as a potential therapeutic target, influencing the progression of various non-metabolic diseases such as kidney diseases, cancer, neurodegenerative disorders, aging, and bone-related diseases. The metabolic pathways involved in lipid metabolism are complex and highly interconnected. Although the abundance of metabolic targets presents opportunities for lipid metabolism regulation, the limited precision and safety of traditional therapeutic approaches remain significant challenges. These limitations have catalyzed the development of multifunctional nano-delivery platforms aimed at targeted intervention in lipid metabolic processes, further enhancing the flexibility of lipid metabolism regulation. This review outlines the latest advancements and representative applications of these multifunctional nano-delivery platforms. Notably, extensive research has been conducted on nanoparticles and liposomes, with these technologies being relatively mature. Furthermore, numerous novel biomaterials, including engineered adipocytes, exosome vesicles secreted by natural cells, smart-responsive nanomicelles, composite hydrogels, and engineered lipid droplets, are being increasingly explored. Finally, the review discusses the advantages of drug delivery strategies based on the targeted intervention of lipid metabolic processes, the limitations of current technologies, promising future research directions, and treatment challenges.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"87"},"PeriodicalIF":29.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12676797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677308","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":"Cell-free DNA in sepsis: from molecular insights to clinical management.","authors":"Lei Li, Hong-Chao Huang, Yin He, Jia-Yue-Cheng Pang, Shi-Chu Xiao, Zhao-Fan Xia, Yong-Jun Zheng","doi":"10.1186/s40779-025-00668-2","DOIUrl":"10.1186/s40779-025-00668-2","url":null,"abstract":"<p><p>Sepsis is a dysregulated host response to infection that frequently results in fatal multiple organ dysfunction. Despite advances in clinical identification and management, both its incidence and mortality have remained persistently high. Emerging evidence indicates that cell-free DNA (cfDNA), as a novel biomarker and molecular therapeutic target, holds promise for improving the clinical management of sepsis. cfDNA refers to DNA fragments present in body fluids, including naked DNA, membrane-coated DNA, nucleosomes, and neutrophil extracellular traps (NETs). cfDNA is released from host cells or pathogens into body fluids through pathways, such as NETosis, mitochondrial damage, cell necrosis, apoptosis, pyroptosis, and erythroblast enucleation. The released cfDNA triggers a strong inflammatory response by activating Toll-like receptor (TLR) 9, the absent in melanoma 2 (AIM2) inflammasome, and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. At the same time, cfDNA activates the coagulation cascade and inhibits anticoagulant and fibrinolytic systems through multiple mechanisms, resulting in microcirculatory disorders. These pathological effects are closely associated with sepsis-related organ dysfunction and poor prognosis. Elucidation of the release and pathological mechanisms of cfDNA provides a foundation for the development of targeted treatment strategies. Currently, molecular therapeutic approaches targeting cfDNA, including peptidylarginine deiminase (PAD) 4 inhibitors, pore-forming inhibitors, antioxidants, cfDNA scavengers, and deoxyribonucleases (DNases), have shown certain efficacy in treating sepsis and systemic inflammation. In terms of sepsis monitoring, compared with traditional markers, cfDNA exhibits extremely high timeliness and dynamic monitoring capability. cfDNA can simultaneously indicate the complex interplay among infection, host response, and organ damage, making it suitable for early diagnosis, prognosis assessment, treatment monitoring, organ function evaluation, and pathogen detection. Given its broad application prospects in the diagnosis and treatment of sepsis, this paper systematically elaborates on the mechanisms of cfDNA release and pathological effects in sepsis, reviews progress in cfDNA-targeted monitoring and therapeutic strategies, discusses technical challenges, and outlines potential future directions.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"85"},"PeriodicalIF":29.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12670778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654946","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":"Sepsis in burns: lessons learned, challenges remain.","authors":"Folke Sjöberg, David Greenhalgh, Moustafa Elmasry, Ahmed T El-Serafi, Ingrid Steinvall","doi":"10.1186/s40779-025-00677-1","DOIUrl":"10.1186/s40779-025-00677-1","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"86"},"PeriodicalIF":22.9,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12670787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654938","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":"β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition.","authors":"Xiao-Xu Wang, Wei-Jie Zhong, Jie-Mei Li, Di Wang, Shuang-Qin Chen, Jin-Hua Miao, Wei-Wei Shen, Xiao-Long Li, Jie-Wu Huang, Shan Zhou, Cheng Wang, Jun Ai, Li-Li Zhou","doi":"10.1186/s40779-025-00669-1","DOIUrl":"10.1186/s40779-025-00669-1","url":null,"abstract":"<p><strong>Background: </strong>Peritoneal fibrosis represents a major clinical challenge for end-stage renal disease (ESRD) patients when they are undergoing peritoneal dialysis (PD). Single-cell RNA sequencing identified that peritoneal mesothelial cells undergo a senescence fate transition in long-term PD patients. Whereas the existence of mesothelial cell senescence and the underlying mechanisms should be thoroughly explored.</p><p><strong>Methods: </strong>To further investigate mesothelial cell senescence, we utilized a clinical cohort comprising dialysate effluents from PD patients and peritoneal biopsy specimens, peritoneal dialysis fluid (PDF)-induced mouse models, and cultured primary mesothelial cells. Single-cell RNA sequencing, transcriptome sequencing, immunofluorescence, Western blotting, and other analyses were administered. To validate the critical role of β-catenin in mesothelial cell senescence, β-catenin knockout mice were employed. Additionally, the senolytic drugs dasatinib plus quercetin were administered to PDF mice to assess the key role of mesothelial cell senescence in peritoneal fibrosis.</p><p><strong>Results: </strong>Single-cell RNA sequencing demonstrated that mesothelial cells derived from long-term PD patients are major trend to senescence fate. Moreover, β-catenin signaling was significantly upregulated, as well as transforming growth factor-β (TGF-β) pathways. We observed that senescent mesothelial cells were highly increased in both dialysate effluent and peritoneal biopsies of long-term PD patients. In dialysate effluent, matrix metalloproteinase-7 (MMP-7), an indicator of downstream targets of β-catenin, was positively correlated with TGF-β1. Both biomarkers were also positively associated with PD duration. Mechanistically, we found that β-catenin promotes dynamin-related protein 1 (Drp1) expression, a key mediator of mitochondrial fission, thereby inducing mesothelial cell senescence. Then, TGF-β1 was secreted to activate the Smad signaling pathway in fibroblasts, leading to myofibroblast activation and subsequent peritoneal fibrosis. Notably, administration of senolytic drugs, dasatinib plus quercetin, significantly alleviated peritoneal fibrosis regardless of treatment timing.</p><p><strong>Conclusion: </strong>Targeting β-catenin signaling and mesothelial cell senescence may represent potential therapeutic interventions for preventing peritoneal fibrosis.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"83"},"PeriodicalIF":29.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649108","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":"Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels-Alder reaction-based self-immolative molecular cage strategy.","authors":"Meng-Die Yang, Kang Fang, Xiao-Yi Zhang, Gang Yang, He-Qing Yi, Le Cai, Shan-Shan Qin, Xin-Da Yang, Rong Rong, Shuo Shi, Fei Yu","doi":"10.1186/s40779-025-00673-5","DOIUrl":"10.1186/s40779-025-00673-5","url":null,"abstract":"<p><strong>Background: </strong>Targeted alpha therapy (TAT) has emerged as a promising strategy for cancer treatment by selectively delivering high linear energy transfer (LET) alpha-emitters to tumor cells while minimizing off-target toxicity. However, the clinical translation of alpha-emitters, particularly radium-223 (²²³Ra), remains challenging due to inefficient targeted delivery and uncontrolled release of recoil daughter products, leading to systemic toxicity.</p><p><strong>Methods: </strong>Herein, a dual-locked pretargeted strategy was developed integrating platinum^IV (Pt^IV)-loaded hydrogel nanoparticles (HNPs) (HAQ@HNPs) and ²²³Ra-loaded HNPs (²²³Ra@HNPs) into an inverse electron demand Diels-Alder (IEDDA)-activated drug delivery system. In vitro cytotoxicity, ROS, and apoptosis, together with in vivo biodistribution, imaging, and therapeutic studies, were performed to evaluate the therapeutic efficacy and immune activation.</p><p><strong>Results: </strong>This caged dual-locked approach enables precise pretargeted accumulation at the tumor site, followed by rapid dissociation and controlled release of ²²³Ra and Pt^IV upon IEDDA-triggered activation, thereby ensuring high tumor specificity while minimizing systemic exposure. The synergistic combination of TAT and chemotherapy effectively disrupts redox homeostasis, induces immunogenic cell death (ICD), and elicits a robust antitumor immune response. Furthermore, when combined with programmed death-ligand 1 (PD-L1) blockade, this strategy significantly enhances systemic antitumor immunity, leading to robust inhibition of tumor growth and metastasis.</p><p><strong>Conclusions: </strong>These findings underscore the potential of dual-locked pretargeted strategies to advance TAT by improving therapeutic efficacy and addressing the critical challenge of radionuclide leakage, paving the way for next-generation precision-targeted radiopharmaceuticals.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"84"},"PeriodicalIF":29.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648964","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":"Effectiveness and cost-effectiveness of risk-adapted colorectal cancer screening: a randomized controlled trial and modeling analysis.","authors":"Hong-Da Chen, Bin Lu, Ju-Fang Shi, Yue-Yang Zhou, Ling-Bin Du, Xian-Zhen Liao, Dong-Hua Wei, Dong Dong, Yi Gao, Chen Zhu, Rong-Biao Ying, Wei-Fang Zheng, Shi-Peng Yan, Hai-Fan Xiao, Juan Zhang, Yun-Xin Kong, Fu-Rong Li, Na Li, Jia-Hui Luo, Chen-Yu Luo, Hermann Brenner, Min Dai","doi":"10.1186/s40779-025-00671-7","DOIUrl":"10.1186/s40779-025-00671-7","url":null,"abstract":"<p><strong>Background: </strong>Risk-adapted colorectal cancer (CRC) screening has the potential to balance effectiveness with resource demands, yet evidence comparing it with established methods remains limited. This study aims to compare outcomes of risk-adapted CRC screening with colonoscopy and fecal immunochemical test (FIT) strategies.</p><p><strong>Methods: </strong>We adopted a hybrid methodology combining real-world data from a population-based CRC screening randomized controlled trial (TARGET-C) with projections from a validated Markov-based microsimulation model (MIMIC-CRC). The TARGET-C trial enrolled 19,582 participants aged 50-74 years from 6 centers in China, randomized in a 1:2:2 ratio into 3 groups. After applying the exclusion criteria, the final analysis included 3883 participants in the one-time colonoscopy group, 7793 in the annual FIT group, and 7697 in the risk-adapted screening group. In the latter group, screening allocation was determined by a composite risk score incorporating age, sex, family history of CRC, smoking status, and body mass index, with high-risk participants referred for colonoscopy and low-risk participants for FIT. The primary outcome was detection rates of advanced neoplasm (CRC and advanced adenoma) over 4 rounds. Secondary outcomes included screening participation, colonoscopy demand, and costs from a societal perspective. Long-term effectiveness and cost-effectiveness were modeled over 15 years using MIMIC-CRC.</p><p><strong>Results: </strong>Across 4 rounds, overall participation rates (attending at least one screening round) were 42.3% (colonoscopy), 99.8% (FIT), and 92.5% (risk-adapted). Detection rates of advanced neoplasms were 2.8%, 2.3%, and 2.6%, respectively, with no significant differences (P > 0.05). Colonoscopies needed to detect 1 advanced neoplasm were 15.4, 7.9, and 9.3, respectively. From a societal perspective, the cost for detecting 1 advanced neoplasm was 15,341, 21,754, and 24,300 Chinese Yuan, respectively. Over 15 years, risk-adapted screening reduced incidence by 16.7% and mortality by 21.5% compared with no screening, slightly less effective than colonoscopy (24.6% and 24.8%, respectively). Under observed real-world adherence, colonoscopy was the most cost-effective; under perfect full adherence, risk-adapted screening was the most cost-effective.</p><p><strong>Conclusions: </strong>In this population-based CRC screening trial, risk-adapted screening, colonoscopy, and FIT demonstrated comparable effectiveness, but differed in participation rates, resource utilization, and cost-effectiveness. Risk-adapted screening could serve as a complementary approach to established strategies, particularly when health resources are limited.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry (ChiCTR1800015506).</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"82"},"PeriodicalIF":29.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12642085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596651","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 emerging role of ferroptosis in the pathological development and progression of sepsis.","authors":"Hui-Ting Zhou, Jie Huang, Ya-Kun Liu, Jiang-Huai Wang, Jian Wang","doi":"10.1186/s40779-025-00665-5","DOIUrl":"10.1186/s40779-025-00665-5","url":null,"abstract":"<p><p>Ferroptosis, a form of iron-dependent regulated cell death (RCD), is emerging as a critical mechanism in the pathogenesis and progression of sepsis. This review highlights the intricate molecular pathways and hallmark features of ferroptosis, including lipid peroxidation, dysregulation of iron metabolism, and glutathione depletion, which exacerbate sepsis progression and sepsis-associated multi-organ damage. The systemic interactions of ferroptosis with inflammation, innate, and adaptive immunity, and organ injury are elucidated, emphasizing the role ferroptosis plays both in immunity including sepsis-associated immune cell damage/dysfunction, immune dysregulation, and immunosuppression, and in sepsis-associated multi-organ injury such as acute lung injury (ALI), acute kidney injury (AKI), acute hepatic injury (AHI), acute intestinal injury, septic cardiomyopathy, and septic encephalopathy. Therapeutic strategies targeting ferroptosis hold promise for improving sepsis outcomes. Approaches include pharmacological interventions of ferroptosis-associated pathways, nanoparticle-based delivery systems, and combinatorial therapies aimed at preventing immune dysfunction and protecting against multi-organ failure. Nonetheless, challenges remain in translating preclinical findings into clinical application, necessitating further research into ferroptosis-specific regulatory networks. This review underscores the potential of therapeutics targeting ferroptosis as a transformative approach to addressing sepsis, paving the way for innovative and precision-based clinical interventions.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"81"},"PeriodicalIF":29.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12625605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541389","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":"Challenges, opportunities, and future perspectives of portable field endoscopy.","authors":"Ke He, Shu-Yi Wang, Jun Ren","doi":"10.1186/s40779-025-00666-4","DOIUrl":"10.1186/s40779-025-00666-4","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"80"},"PeriodicalIF":29.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12621382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541393","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":"Diverging global incidence trends of early-onset cancers: comparisons with incidence trends of later-onset cancers and mortality trends of early-onset cancers.","authors":"Miyu Terashima, Kota Nakayama, Sora Shirai, Satoko Ugai, Hwa-Young Lee, Haruna Matsui, Hiroki Mizuno, Shiori Tanaka, Minkyo Song, Naoko Sasamoto, Ichiro Kawachi, Edward L Giovannucci, Tomotaka Ugai","doi":"10.1186/s40779-025-00670-8","DOIUrl":"10.1186/s40779-025-00670-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The global increase in the incidence of early-onset cancers (defined as cancers diagnosed at 20-49 years old) is a serious public health problem. We investigated 1) whether the incidence trend of early-onset cancers differs from that of later-onset cancers and 2) whether both the incidence and mortality of early-onset cancers have increased concurrently.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We utilized age-standardized incidence and mortality rates for early-onset and later-onset cancers diagnosed between 2000 and 2017 from the Cancer Incidence in Five Continents and World Health Organization (WHO) mortality databases. The national obesity prevalence among adults aged 20-49 years was obtained from the National Clinical Database. Using joinpoint regression models, we calculated average annual percentage changes (AAPCs) for cancer incidence and mortality by cancer types and countries. We additionally conducted human development index (HDI)-stratified analyses and assessed the correlation between the obesity prevalence in younger populations and early-onset cancer incidence by country. To investigate the more recent trend of early-onset cancer mortality, we extended our mortality analysis after 2017 for cancer types and countries with statistically significant positive AAPCs in both incidence and mortality of early-onset cancers between 2000 and 2017.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our analysis showed that 10 early-onset cancer types (thyroid cancer, breast cancer, melanoma, uterine cancer, colorectal cancer, kidney cancer, cervical cancer, pancreatic cancer, multiple myeloma, Hodgkin lymphoma) in females and 7 early-onset cancer types (thyroid cancer, kidney cancer, testis cancer, prostate cancer, colorectal cancer, melanoma, leukemia) in males had statistically significant positive AAPCs in at least 10 countries. Among these, the following early-onset cancer types had significantly higher AAPCs than later-onset cancer types in females: colorectal cancer (6 countries; AAPC range: 1.8-3.8%), cervical cancer (6 countries; AAPC range: 1.2-3.3%), pancreatic cancer (5 countries; AAPC range: 2.3-13.0%), and multiple myeloma (5 countries; AAPC range: 3.1-9.8%); in males: prostate cancer (12 countries; AAPC range: 3.9-18.4%), colorectal cancer (8 countries; AAPC range: 1.8-3.2%), and kidney cancer (6 countries; AAPC range: 2.0-6.0%). We observed statistically significant positive AAPCs in both the incidence and mortality of the following early-onset cancer types: uterine cancer (5 countries) and colorectal cancer (3 countries in females and 5 countries in males). The steeper increases in early-onset cancers compared with later-onset cancers were mainly observed in the very high-HDI country group, including early-onset colorectal cancer (AAPC = 2.4%, 95% CI 2.1-2.6 in females; AAPC = 2.0%, 95% CI 1.7-2.4 in males) to later-onset colorectal cancer (AAPC = -0.1%, 95% CI -0.2 to 0 in females; AAPC = -0.2%, 95% CI -0.3 to 0 in males)","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"79"},"PeriodicalIF":29.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12616995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523886","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":"TNC-targeted CAR-macrophage therapy alleviates liver fibrosis in mice.","authors":"Kai-Zhao Chen, Zi-Yang Lin, Long-Jun Chen, You-Xi Zhou, Wei Zhang, Hao-Yang Wan, Yong-Kun Huo, Qi Fu, Zi-Qing Gao, Hong-Wei Cheng, Xiao-Dong Ma, Shuai-Shuai Zhang","doi":"10.1186/s40779-025-00667-3","DOIUrl":"10.1186/s40779-025-00667-3","url":null,"abstract":"<p><strong>Background: </strong>Tenascin-C (TNC) is an extracellular matrix (ECM) protein involved in tissue damage and fibrosis. Chimeric antigen receptor (CAR) cell therapy is a novel therapeutic approach that has attracted increasing attention in recent years. Here, we engineered CAR-macrophages targeting TNC (TNC-CAR-Ms) and explored the underlying mechanism through which TNC-CAR-Ms treat liver fibrosis.</p><p><strong>Methods: </strong>The role of TNC in liver fibrosis was studied in established Tnc knockout (KO) and littermate control mice. A TNC-targeted single-chain variable fragment (scFv) was designed to generate TNC-CAR-Ms and evaluate their biological function. The phagocytosis and killing effects of TNC-CAR-Ms were tested in vitro, while the antifibrotic efficacy and safety of TNC-CAR-Ms were evaluated in vivo. The underlying mechanism through which TNC-CAR-Ms treat liver fibrosis was investigated by Western blotting, flow cytometry, and RNA sequencing.</p><p><strong>Results: </strong>TNC expression was significantly upregulated in the liver and activated hepatic stellate cells (HSCs) in carbon tetrachloride (CCl₄)-treated mice. Animal studies showed that Tnc KO protects mice from CCl₄-induced liver damage and fibrosis. Upon demonstrating their ability to engulf and kill activated HSCs, we intravenously administered TNC-CAR-Ms to fibrotic mice and found that TNC-CAR-Ms significantly reduced liver fibrosis. Mechanistically, TNC-CAR-Ms specifically migrated to liver tissues, potently reduced TNC expression, and decreased the activity of the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) and integrin/focal adhesion kinase (FAK) signaling pathway. In addition, TNC-CAR-Ms significantly modified the hepatic immune microenvironment, characterized mainly by an increase in the numbers of M2-polarized macrophages and CD8⁺ T cells in the liver. Finally, in CCl₄-treated mice, the depletion of CD8⁺ T cells with an anti-CD8α antibody significantly impaired the antifibrotic effect of TNC-CAR-Ms.</p><p><strong>Conclusions: </strong>Our proof-of-concept study demonstrates the therapeutic potential of TNC-CAR-Ms in alleviating liver fibrosis and may inform the development of future therapeutic strategies for the treatment of a range of liver diseases with a fibrotic phenotype.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"12 1","pages":"78"},"PeriodicalIF":29.0,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12604166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489412","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}