Translational research : the journal of laboratory and clinical medicine最新文献

{"title":"β2-Microglobulin and the Ageing Brain.","authors":"Yanwei You","doi":"10.1016/j.trsl.2026.05.001","DOIUrl":"https://doi.org/10.1016/j.trsl.2026.05.001","url":null,"abstract":"<p><p>β2-microglobulin (β2M) has long been treated as a generic marker of immune activation, kidney function, or cancer prognosis. However, emerging mechanistic evidence suggests that β2M may actively contribute to brain ageing by influencing neurogenesis, synaptic function, and cognitive performance. This study conducted a knowledge-mapping analysis, showing that β2M research is highly fragmented across themes including haematologic malignancy prognosis, systemic inflammation and cytokine networks, cerebrospinal fluid biomarkers, and neurodegeneration. By integrating keyword clustering, co-occurrence structure, and burst detection, the analysis supports reframing β2M as a cross-context biomarker candidate for the ageing brain and outlines a research roadmap. The key next step is to determine whether β2M acts as a causal driver, a circulating ageing signal, or a context-dependent modifier across brain-ageing contexts. Priorities include harmonised measurement and reporting, stronger multi-compartment evidence linking peripheral and central β2M, longitudinal brain-ageing endpoints, and study designs that incorporate modifiable lifestyle-related risk architecture to improve comparability and translational value in immune-brain ageing research.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Importin-7 Facilitates Cervical Cancer Progression Through MSI2 Nuclear Import and Is Associated With MSI2-MYC-Linked Glycolytic Reprogramming.","authors":"Wanzhen Zhou, Qinyang Xu, Tian Qiu, Juan Wang, Jing Chen, Rongzhen Jiang, Yincheng Teng, Li Ma, Yun Bai, Rui Zhang","doi":"10.1016/j.trsl.2026.04.007","DOIUrl":"https://doi.org/10.1016/j.trsl.2026.04.007","url":null,"abstract":"<p><strong>Background: </strong>Cervical cancer (CC) remains a major cause of cancer-related mortality in women. This study aimed to clarify the oncogenic role and underlying mechanism of Importin-7 (IPO7), a nuclear transport protein, in CC progression.</p><p><strong>Methods: </strong>TCGA and GEO datasets were analyzed, with experimental validation in CC cell lines and xenograft mouse models. IPO7 function was assessed through RNA interference, followed by evaluations of cell proliferation, apoptosis, migration, invasion, and tumor growth. Mass spectrometry identified IPO7 cargo. Molecular interactions were investigated by co-immunoprecipitation, nuclear/cytoplasmic fractionation, ubiquitination assays, and nuclear localization signal (NLS) mutagenesis. RNA sequencing, Seahorse flux analysis, and Western blotting were used to assess downstream transcriptomic and metabolic changes.</p><p><strong>Results: </strong>IPO7 was significantly upregulated in CC and correlated with advanced disease stage and poor prognosis. IPO7 knockdown impaired tumor growth in vitro and in vivo. MSI2 was identified as a direct nuclear cargo of IPO7, with binding dependent on its NLS. IPO7 promoted nuclear translocation of MSI2 and prevented its ubiquitin-mediated cytoplasmic degradation. MSI2 silencing abrogated the oncogenic effects of IPO7. High co-expression of IPO7 and MSI2 was associated with the worst patient outcomes. Mechanistically, IPO7, MSI2, and c-MYC formed a ternary complex that promoted MSI2-dependent nuclear accumulation of c-MYC and enhanced c-MYC mRNA stability. Disruption of this axis suppressed MYC-linked metabolic programs, including reduced glycolytic activity in CC cells.</p><p><strong>Conclusions: </strong>IPO7 facilitates CC progression by mediating MSI2 nuclear import and enhancing c-MYC-dependent transcriptional programs. This axis is associated with metabolic reprogramming, including a glycolysis-related signature in CC. The IPO7-MSI2-MYC axis represents a novel prognostic marker and therapeutic target in CC.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing Eravacycline as an Immunomodulator for Immunodeficiencies Driven by Anti-IFN-γ Autoantibodies.","authors":"Yu-Ting Yen, Yi-Hua Pan, Po-Ju Hsiao, Tzu-Tang Wei, Yan-Tung Kiu, Ru-Sing Lee, Yu-Chung Chuang, Jann-Tay Wang, Wang-Huei Sheng, Yee-Chun Chen, Shan-Chwen Chang, Un-In Wu","doi":"10.1016/j.trsl.2026.04.006","DOIUrl":"https://doi.org/10.1016/j.trsl.2026.04.006","url":null,"abstract":"<p><strong>Introduction: </strong>Adult-onset immunodeficiency (AOID) driven by pathogenic anti-interferon-γ (IFN-γ) autoantibodies (AIGA) mimics inborn errors of IFN-γ signaling, causing life-threatening nontuberculous mycobacterial and fungal infections. Current B-cell depletion or prolonged antimicrobials fail to directly reverse autoantibody-mediated IFN-γ blockade. We hypothesized that small molecules binding AIGA-targeted IFN-γ epitopes could sterically disrupt pathogenic autoantibody-cytokine complexes and restore JAK-STAT1 signaling.</p><p><strong>Methods: </strong>We conducted structure-based high-throughput virtual screening of an FDA-approved drug library using the IFN-γ/IFNGR1 crystal structure (PDB: 1FG9). Compounds predicted to bind AIGA-targeted IFN-γ epitopes were selected for functional testing for their ability to restore IFN-γ signaling inhibited by patient plasma containing AIGA. Patients were stratified into drug-free remission or non-remission groups for comparative analyses.</p><p><strong>Results: </strong>Eravacycline, a tetracycline antibiotic, was identified as a lead candidate with high predicted affinity (-9.1 kcal/mol) for AIGA-targeted IFN-γ epitopes. In functional assays, eravacycline dose-dependently restored IFN-γ-induced STAT1 phosphorylation inhibited by AIGA, outperforming tigecycline under the same conditions (p < 0.001), and partially reversed AIGA-mediated suppression of CXCL9 (p < 0.01) and TNF-α (p < 0.001) expression. These effects were observed in both drug-free remission and non-remission groups.</p><p><strong>Conclusions: </strong>Eravacycline is the first tetracycline shown to break pathogenic autoantibody-cytokine protein-protein interactions in human disease, restoring Th1 immunity ex vivo. These findings establish proof-of-concept for structure-guided reversal of anti-cytokine autoantibody pathogenicity using an FDA-approved antimicrobial, offering a rapidly translatable dual-action therapy for AIGA-driven AOID and potentially other anti-cytokine autoantibody syndromes.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoprotective effects of the neuropeptide VIP: insights from triple cultures of human osteocytes, osteoblasts, and osteoclasts.","authors":"David Castro-Vázquez, Iván García-López, Katharina Wirsig, Paula Arribas-Castaño, Rosa P Gomariz, Carmen Martínez, Yasmina Juarranz, Anne Bernhardt, Mar Carrión","doi":"10.1016/j.trsl.2026.04.004","DOIUrl":"10.1016/j.trsl.2026.04.004","url":null,"abstract":"<p><p>Bone remodelling is a dynamic process of osteoblastic bone formation and osteoclastic bone resorption, regulated by local, paracrine and endocrine factors, in which osteocytes act as orchestrators of bone homeostasis. Among these regulatory factors, the neuropeptide VIP (vasoactive intestinal peptide) has demonstrated osteoprotective effects by inhibiting osteoclastogenesis and promoting osteoblast differentiation. However, its potential role in osteocyte biology remains unexplored. In this study, we investigated the effect of VIP on the differentiation of primary human osteocytes. We describe for the first time the expression of VIP and its receptors during in vitro osteocyte differentiation. Our results show that VIP promotes osteocytogenesis, accompanied by a reduction in the RANKL/OPG ratio, thereby supporting its role as an anti-osteoclastogenic factor. To better mimic the complexity of bone tissue, we performed triple co-cultures of osteoblasts and simultaneously differentiating osteocytes and osteoclasts, in the presence or absence of VIP. Our results confirmed that VIP supports the osteoblast-to-osteocyte transition and promotes an osteoprotective phenotype, characterized by a reduced RANKL/OPG ratio and decreased SOST expression. The downregulation of sclerostin may attenuate osteocyte-mediated inhibitory signalling toward osteoblasts and, in turn, contribute to the reduction of the osteoblastic RANKL/OPG ratio. Collectively, our findings reinforce the anti-osteoclastogenic actions of VIP, supporting its role as a potential osteoprotective factor.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"40-51"},"PeriodicalIF":5.9,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The eicosanoid-cell death axis: A mechanistic review of crosstalk in health and disease.","authors":"Woo Hyun Park","doi":"10.1016/j.trsl.2026.04.005","DOIUrl":"10.1016/j.trsl.2026.04.005","url":null,"abstract":"<p><p>Eicosanoids, a diverse family of lipid mediators from arachidonic acid (AA), are fundamental regulators of inflammation and cellular signaling. Concurrently, regulated cell death (RCD) pathways-including apoptosis, necroptosis, pyroptosis, and ferroptosis-are essential, genetically encoded programs that maintain tissue homeostasis by eliminating damaged or unwanted cells. A growing body of evidence reveals that these two systems are not independent but are deeply and mechanistically intertwined, forming a critical axis that dictates cell fate. Through a systematic evaluation of current literature, this review synthesizes the multifaceted nature of this crosstalk. An analysis is presented of the molecular mechanisms by which cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E₂ (PGE₂), exert a dual influence on apoptosis, promoting survival in cancer while triggering death in immune cells. The temporal regulation of immunogenic cell death (ICD) is further explored, wherein lipoxygenase (LOX)-derived leukotrienes amplify lytic death pathways, while specialized pro-resolving mediators (SPMs) suppress them to restore homeostasis. A central focus is the paradigm-shifting discovery of LOX enzymes as direct executioners of ferroptosis, an iron-dependent form of RCD driven by catastrophic lipid peroxidation. Crucially, this review expands upon previously overlooked intracellular mediators, explicitly detailing how eicosanoid-driven oxidative stress and mitochondrial dysfunction act as fundamental convergence points for RCD modulation. Furthermore, emerging RCD modalities such as PANoptosis and cuproptosis are discussed to highlight the expanding landscape of this crosstalk. Dysregulation of this eicosanoid-RCD axis is a key driver in pathologies ranging from cancer and chronic autoimmunity to neurodegenerative diseases and cardiovascular disorders. By systematizing these molecular touchpoints, this review highlights emerging therapeutic strategies aimed at precisely targeting this nexus to restore homeostasis and treat human disease.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"52-63"},"PeriodicalIF":5.9,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The key role of cellular plasticity in the development of colorectal cancer.","authors":"Lingqiao Lou, Yanghui Cao, Zhiyuan Ma, Bei Ji, Shuhui Liu, Kenichi Mizuno, Shuji Terai, Biguang Tuo, Taolang Li, Xuemei Liu","doi":"10.1016/j.trsl.2025.12.002","DOIUrl":"10.1016/j.trsl.2025.12.002","url":null,"abstract":"<p><p>The development of colorectal cancer, which is a malignant tumor demonstrating high morbidity and mortality worldwide, involves complex molecular mechanisms and biological processes. Early-stage colorectal cancer patients do not exhibit obvious clinical symptoms; thus, they are often diagnosed with middle-stage to late-stage disease. The overall survival of advanced colorectal cancer patients with metastasis and treatment resistance is poor. Notably, tumor cell plasticity promotes tumorigenesis, metastasis, and therapeutic resistance, thus leading to the high incidence and mortality of colorectal cancer. In-depth studies of cellular plasticity are expected to lead to the identification of new therapeutic targets. In this review, we systematically summarize the role of cellular plasticity in colorectal cancer development and explore the regulatory mechanisms associated with cellular plasticity in colorectal cancer, with the aim of providing a theoretical basis for the development of innovative therapeutic strategies for this type of cancer.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"40-47"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intermittent caloric restriction protects against diabetic heart inflammation via GSDMD-dependent sFRP2-ATF6-NF-κB pathway.","authors":"Kaibin Lin, Changlin Zhai, Ai Wang, Yang Lan, Yun Zhao, Qiwei Zhai, Junbo Ge, Yan Yan","doi":"10.1016/j.trsl.2025.05.006","DOIUrl":"10.1016/j.trsl.2025.05.006","url":null,"abstract":"<p><strong>Background: </strong>Calorie restriction holds the potential in alleviating metabolic disorders and inflammation. However, the effects of intermittent caloric restriction (ICR) on cardiometabolic diseases remain poorly understood. In this study, we aimed to assess the protective role of ICR in both prediabetic and diabetic heart injury.</p><p><strong>Methods: </strong>Prediabetic and diabetic models were established using a high-fat diet and high-fat diet/streptozotocin in mice, respectively. Following the induction of prediabetes mellitus and diabetes mellitus, ICR was implemented to evaluate its therapeutic effect. As alterations of gasdermin D (GSDMD) expression were monitored, we investigated the relationship between the cardioprotective effect of ICR and GSDMD using human heart samples, GSDMD knockout mice and adeno-associated virus 9(AAV9). Through RNA-sequencing, the underlying mechanism of GSDMD-mediated diabetes-associated cardiac inflammation was further elucidated.</p><p><strong>Results: </strong>Our study indicated that ICR prevented cardiac dysfunction by alleviating cardiac lipid overaccumulation in prediabetic mice. Conversely, the effect of ICR on lipid overaccumulation were limited in diabetic mice. Instead, the cardioprotective effect of ICR was mediated through the inhibition of GSDMD-mediated cardiomyocyte pyroptosis and inflammation response in diabetic mice. In human hearts, the expression level of GSDMD were positively correlated with diabetes-induced heart injuries. Furthermore, GSDMD deficiency mimicked the cardioprotective effects of ICR, while GSDMD overexpression in cardiomyocytes offset the cardioprotective effect of ICR in diabetic mice. Mechanistically, the upregulation of GSDMD activated secreted Frizzled-related protein 2 (sFRP2)/ATF6/NF-κB pathway, exacerbating cardiac inflammation in diabetic hearts. Moreover, the replenishment of recombinant sFRP2 offset the cardiac benefits of GSDMD deficiency in diabetic mice.</p><p><strong>Conclusions: </strong>Our study demonstrated the prevention of prediabetic and diabetic heart injury by ICR were mediated by alleviating cardiac lipid overaccumulation and inflammation, respectively. Moreover, targeting GSDMD-dependent sFRP2/ATF6/ NF-κB pathway conferred the cardioprotective effects of ICR and could serve as a potential therapeutic strategy for diabetic heart failure.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"59-76"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hierarchical multimodal structural and material analysis of bone in diabetes.","authors":"Ashu Rastogi, Raveena Singh, Saroj Kumar, Srinivas Seshabhattaru, Rajesh Kesavan, Uttam Chand Saini, Navin Kumar, Sanjay Kumar Bhadada","doi":"10.1016/j.trsl.2025.11.004","DOIUrl":"10.1016/j.trsl.2025.11.004","url":null,"abstract":"<p><strong>Objective: </strong>Diabetic neuropathy and Charcot neuroarthropathy (CN) may compromise lower limb skeletal integrity. We performed a comprehensive comparative assessment of foot bone across multiple hierarchical parameters at nano, meso and micro scale orders.</p><p><strong>Research design and methods: </strong>Calcaneal bone specimens obtained from individuals with CN (Group A; n = 12), diabetic neuropathy (Group B; n = 21), and healthy controls (Group C; n = 18). Trabecular microarchitecture was assessed using micro-computed tomography (micro-CT), mechanical strength through uniaxial compression, biochemical composition by infrared spectroscopy (FTIR), crystal dimensions with X-ray diffraction (XRD), tissue-level mechanical behaviour by nanoindentation and quantiative organic and mineral content of bone matrix by thermogravimetric analysis (TGA).</p><p><strong>Results: </strong>Micro-CT revealed 35.9 % reduced trabecular thickness (0.25 ± 0.11 mm vs 0.39 ± 0.14 mm, p = 0.016), 57 % lower maximum load tolerance (218.85 ± 18.84 N vs 508.15 ± 100.98 N, p < 0.001) and 55 % reduced stiffness (51.62 ± 4.89 N/mm vs. 114.63 ± 13.74 N/mm, p < 0.001) in Group A compared to Group C, respectively. Mineral-to-matrix ratio (3.17 ± 0.68 vs. 4.75 ± 1.47, p < 0.001), collagen maturity index (1.25± 0.29 vs. 1.74 ± 0.50, p < 0.001) and organic fraction (44.95 ± 5.15 % vs 50.91 ± 4.85 %;p = 0.005) were lower in Group A compared to group C, respectively. The elastic modulus (8.13 ± 1.57 GPa vs. 18. 12± 1.96 GPa) and hardness (0.34 ± 0.07 GPa vs. 0.71 ± 0.13 GPa) were significantly reduced in group A compared to Group C (p < 0.001 for both), confirming compromised tissue-level mechanics of foot bones in CN. Bone samples from Group B showed intermediate values compared to either group A and C, respectively.</p><p><strong>Conclusion: </strong>Charcot neuroarthropathy of foot is characterised by severe, multiscale impairments in bone architecture, composition, and mechanical function that contribute to heightened skeletal fragility and underscore the need for targeted interventions addressing bone quality.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"1-11"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the ApoB100-ENO1 interaction with engineered peptides attenuates atherosclerotic inflammation and plaque progression.","authors":"Hyun Jung Yoo, Dan Hoang Nguyet Vo, Shin Eui Kang, Sang Jin Lee, Shindy Soedono, Esther Jin Joo, Maria Averia, Kae Won Cho, Yeong Wook Song","doi":"10.1016/j.trsl.2025.12.003","DOIUrl":"10.1016/j.trsl.2025.12.003","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis, a chronic inflammatory disease, presents significant \"residual risk\" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-κB activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression.</p><p><strong>Methods: </strong>We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr^-/- mice fed an atherogenic diet were treated with PP3m to evaluate its effects on atherosclerosis progression, macrophage accumulation, and systemic inflammation.</p><p><strong>Results: </strong>scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68⁺ M1 macrophages. Atherogenic stimuli induced ENO1 translocation to the plasma membrane in macrophages. In vitro, PP3m significantly attenuated inflammatory responses by suppressing IL-6 and CXCL8 secretion, reducing M1 polarization, and dose-dependently inhibiting oxLDL-induced foam cell formation and uptake. In vivo, PP3m reduced aortic lesion area, lipid content, and collagen deposition, accompanied by decreased macrophage accumulation in plaques and lower circulating pro-inflammatory cytokines. Importantly, these effects were independent of changes in plasma lipid profiles.</p><p><strong>Conclusions: </strong>The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"28-39"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-derived exosomal thrombospondin-1 exacerbates endothelial progenitor cell senescence and lung injury via TGF-β/SMAD signaling in COPD.","authors":"Junjuan Lu, Caihong Liu, Ting Yuan, Honghui Yang, Li Zhang","doi":"10.1016/j.trsl.2025.12.004","DOIUrl":"10.1016/j.trsl.2025.12.004","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition primarily caused by inhalation of harmful particles such as tobacco smoke. Cellular senescence serves as a key driver in its pathogenesis. Although endothelial progenitor cells (EPCs) have been shown to alleviate COPD by reducing inflammatory cell infiltration, the role and mechanisms underlying EPC senescence in this disease remain unclear.</p><p><strong>Methods: </strong>A cigarette smoke (CS)-exposed COPD mouse model was established. Lung injury was assessed histologically, with concurrent quantification of neutrophil infiltration and cellular senescence levels in lung tissues. Pearson analysis evaluated the correlation between senescence severity and neutrophil numbers. In vivo neutrophil depletion was achieved using anti-Ly6G antibody, while GW4869 was used to inhibit exosome secretion from COPD-derived neutrophils. Neutrophils were then co-cultured with EPCs to assess their impact on EPC senescence and DNA damage. Proteomic analyses were employed to identify mechanisms of neutrophil-derived exosomes in COPD.</p><p><strong>Results: </strong>COPD mice exhibited significant lung tissue damage, accelerated cellular senescence, and increased neutrophil infiltration. Senescence severity positively correlated with neutrophil proportion. Mechanistically, thrombospondin-1 (TSP-1) was highly expressed in COPD-derived neutrophils. Knockdown of neutrophil-derived exosomal TSP-1 alleviated EPC senescence. Furthermore, TSP-1 expression was regulated by transcription factor FOS, whereas TGF-β inhibition attenuated the promoting effects of TSP-1 overexpression on cellular senescence and lung injury in COPD mice.</p><p><strong>Conclusion: </strong>This study demonstrates that neutrophil-derived exosomal TSP-1 aggravates EPC senescence and lung injury in COPD, revealing the pathogenic role of TSP-1 in disease progression and highlighting its potential as a therapeutic target.</p>","PeriodicalId":94257,"journal":{"name":"Translational research : the journal of laboratory and clinical medicine","volume":" ","pages":"12-27"},"PeriodicalIF":5.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}