Pub Date : 2026-01-01Epub Date: 2025-12-30DOI: 10.1016/j.trsl.2025.12.006
Qianshi Zhang , Jia Hu , Ziqi Liu , Siwen Wu , Fusheng Liu , Yanlin Tan , Chao Wei , Xiaobin Wang , Jing Li
Intervertebral disc degeneration (IDD), a condition characterized by extracellular matrix (ECM) degradation and nucleus pulposus (NP) cell senescence, compromises disc function. The Akt signaling pathway is essential for NP cell viability and ECM homeostasis. This study identifies the serine/threonine kinase PIM3 as significantly downregulated in degenerated human NP tissues. Notably, PIM3 mRNA expression levels were found to be negatively correlated with the clinical severity of IDD (Pfirrmann grade). The functional role of PIM3 was investigated through knockdown and overexpression experiments in human NP cells. PIM3 overexpression restored cell viability, suppressed senescence, and enhanced ECM protein levels in degenerated NP cells, while its knockdown in normal cells produced the opposite results. These protective effects were critically dependent on the kinase activity of PIM3. Mechanistically, PIM3 was found to physically interact with and activate the Akt signaling pathway, thereby regulating downstream molecules, including mTOR and FoxO1, to modulate cell viability and senescence. In an IDD rat model, AAV-mediated PIM3 overexpression improved ECM integrity, reduced senescence and activated the Akt pathway, mitigating disc degeneration. In conclusion, this study establishes PIM3 as a key regulator of NP cell homeostasis that acts through direct engagement with the Akt/mTOR/FoxO1 axis. Its correlation with disease severity and the kinase-dependent nature of its function highlight PIM3 as a promising, mechanistically-defined therapeutic target for treating IDD.
{"title":"PIM3 enhances nucleus pulposus cell function and extracellular matrix integrity via kinase-dependent activation of the Akt/mTOR signaling axis in intervertebral disc degeneration","authors":"Qianshi Zhang , Jia Hu , Ziqi Liu , Siwen Wu , Fusheng Liu , Yanlin Tan , Chao Wei , Xiaobin Wang , Jing Li","doi":"10.1016/j.trsl.2025.12.006","DOIUrl":"10.1016/j.trsl.2025.12.006","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IDD), a condition characterized by extracellular matrix (ECM) degradation and nucleus pulposus (NP) cell senescence, compromises disc function. The Akt signaling pathway is essential for NP cell viability and ECM homeostasis. This study identifies the serine/threonine kinase PIM3 as significantly downregulated in degenerated human NP tissues. Notably, PIM3 mRNA expression levels were found to be negatively correlated with the clinical severity of IDD (Pfirrmann grade). The functional role of PIM3 was investigated through knockdown and overexpression experiments in human NP cells. PIM3 overexpression restored cell viability, suppressed senescence, and enhanced ECM protein levels in degenerated NP cells, while its knockdown in normal cells produced the opposite results. These protective effects were critically dependent on the kinase activity of PIM3. Mechanistically, PIM3 was found to physically interact with and activate the Akt signaling pathway, thereby regulating downstream molecules, including mTOR and FoxO1, to modulate cell viability and senescence. In an IDD rat model, AAV-mediated PIM3 overexpression improved ECM integrity, reduced senescence and activated the Akt pathway, mitigating disc degeneration. In conclusion, this study establishes PIM3 as a key regulator of NP cell homeostasis that acts through direct engagement with the Akt/mTOR/FoxO1 axis. Its correlation with disease severity and the kinase-dependent nature of its function highlight PIM3 as a promising, mechanistically-defined therapeutic target for treating IDD.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"287 ","pages":"Pages 38-54"},"PeriodicalIF":5.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-11-19DOI: 10.1016/j.trsl.2025.11.003
Zhejun Chen , Liqing Ye , Minyan Zhu , Xi Lin , Jiajia Wu , Xiang Zhang , Yifei Wang , Xia Hong , Zhiyu Li , Shouci Hu , Wen Zhang , Peipei Zhang , Hongbo Chen
Background
Acute kidney injury (AKI) has become a global public health problem that seriously endangers human health, the treatment for AKI is mainly supportive and there is no targeted, efficient and low-toxicity treatment.
Methods & Results
Multi-omics including bulk RNA-seq, scRNA-seq, spatial transcriptomics were used to find the high differential expressed genes between con and AKI. While S100a10 was consistently found to be significantly increased in renal tubular epithelial cells after cisplatin and IRI induced AKI compared with normal control. As S100a10 mainly interacts with Anxa2 to form a tetramer complex. The complex inhibitor, A2ti, was found to improve cisplatin and IRI induced AKI, the mechanisms was uncovered by RNA-seq and ChIP-seq data, which shows A2ti may inhibit the p-Stat3/Spp1 signaling, while colivelin, a Stat3 activator, can reverse the protective role of A2ti. In order to further confirm the role of S100a10 within proximal tubule (PT), rAAV-SGLT2-EGFP-shS100a10 virus was used to knock down s100a10 within PT through tail vein injection, and down-regulation of S100a10 can partially improve cisplatin induced AKI through p-Stat3/Spp1 signaling.
Conclusion
It has been consistently found that the S100a10-Anxa2 complex is involved in AKI by regulating p-Stat3/Spp1 through multi-omics analysis and experiment validation.
{"title":"Multi-omics analysis identifies S100a10/Anxa2 complex within proximal tubule aggravates acute kidney injury through p-Stat3/Spp1 signaling","authors":"Zhejun Chen , Liqing Ye , Minyan Zhu , Xi Lin , Jiajia Wu , Xiang Zhang , Yifei Wang , Xia Hong , Zhiyu Li , Shouci Hu , Wen Zhang , Peipei Zhang , Hongbo Chen","doi":"10.1016/j.trsl.2025.11.003","DOIUrl":"10.1016/j.trsl.2025.11.003","url":null,"abstract":"<div><h3>Background</h3><div>Acute kidney injury (AKI) has become a global public health problem that seriously endangers human health, the treatment for AKI is mainly supportive and there is no targeted, efficient and low-toxicity treatment.</div></div><div><h3>Methods & Results</h3><div>Multi-omics including bulk RNA-seq, scRNA-seq, spatial transcriptomics were used to find the high differential expressed genes between con and AKI. While S100a10 was consistently found to be significantly increased in renal tubular epithelial cells after cisplatin and IRI induced AKI compared with normal control. As S100a10 mainly interacts with Anxa2 to form a tetramer complex. The complex inhibitor, A2ti, was found to improve cisplatin and IRI induced AKI, the mechanisms was uncovered by RNA-seq and ChIP-seq data, which shows A2ti may inhibit the p-Stat3/Spp1 signaling, while colivelin, a Stat3 activator, can reverse the protective role of A2ti. In order to further confirm the role of S100a10 within proximal tubule (PT), rAAV-SGLT2-EGFP-shS100a10 virus was used to knock down s100a10 within PT through tail vein injection, and down-regulation of S100a10 can partially improve cisplatin induced AKI through p-Stat3/Spp1 signaling.</div></div><div><h3>Conclusion</h3><div>It has been consistently found that the S100a10-Anxa2 complex is involved in AKI by regulating p-Stat3/Spp1 through multi-omics analysis and experiment validation.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"284 ","pages":"Pages 57-68"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The global incidence rate of Crohn’s disease (CD) is rising, with mesenteric adipose tissue (MAT) playing a pivotal role in CD progression, particularly in fibrosis development. This study aimed to identify key genes in MAT that contribute to CD progression, thereby providing insights for potential therapeutic strategies.
Methods
The CD-related datasets from the GEO database were aggregated to analyze differentially expressed secreted protein genes. Colon tissue and MAT were harvested from CD subjects and healthy subjects, and H&E and Masson staining were used to detect pathological changes. The expression level of the target gene was determined using various methods (including qRT-PCR, IHC, IF, and Western blot). Primary mesenteric adipocytes of CD patients and healthy controls were isolated and cultured, and epiregulin (EREG) expression was intervened to explore its effects on inflammatory cytokine secretion and lipid metabolism. Additionally, an in-vitro co-culture system of primary adipocytes and intestinal epithelial cells (IECs) and an in-vivo 2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced CD rat model were constructed to explore the effect of EREG on CD symptoms and the underlying mechanisms.
Results
EREG was highly expressed in both CD colon tissues and MAT. Overexpression of EREG in adipocytes facilitated the production of inflammatory factors and lipid metabolism, as well as promoted inflammation and fibrosis in co-cultured IECs. In vivo, EREG knockdown effectively alleviated CD symptoms and fibrosis in TNBS-induced CD rats. The underlying mechanism may be mediated by EREG, promoting epithelial-mesenchymal transition (EMT) and the PPARγ signaling pathways in IECs. Inflammatory cytokines TNF-α and IL-17A induced EREG expression in adipocytes from CD patients
Conclusion
The abnormal upregulation of EREG in adipocytes within MAT contributes to the pathogenesis of CD by promoting inflammation and fibrosis. Targeting EREG may offer a novel therapeutic approach for the clinical treatment of CD.
{"title":"Mesenteric adipocytes promote intestinal fibrosis and inflammation in Crohn’s disease through epiregulin (EREG)","authors":"Yawei Zhang , Hengchang Yao , Kailing Xie, Hao Liu, Lichao Yang, Qiang Wu, Baojia Yao, Liangxin Peng, Zhixian Jiang, Qi Sun, Lianwen Yuan","doi":"10.1016/j.trsl.2025.10.001","DOIUrl":"10.1016/j.trsl.2025.10.001","url":null,"abstract":"<div><h3>Background</h3><div>The global incidence rate of Crohn’s disease (CD) is rising, with mesenteric adipose tissue (MAT) playing a pivotal role in CD progression, particularly in fibrosis development. This study aimed to identify key genes in MAT that contribute to CD progression, thereby providing insights for potential therapeutic strategies.</div></div><div><h3>Methods</h3><div>The CD-related datasets from the GEO database were aggregated to analyze differentially expressed secreted protein genes. Colon tissue and MAT were harvested from CD subjects and healthy subjects, and H&E and Masson staining were used to detect pathological changes. The expression level of the target gene was determined using various methods (including qRT-PCR, IHC, IF, and Western blot). Primary mesenteric adipocytes of CD patients and healthy controls were isolated and cultured, and epiregulin (EREG) expression was intervened to explore its effects on inflammatory cytokine secretion and lipid metabolism. Additionally, an <em>in-vitro</em> co-culture system of primary adipocytes and intestinal epithelial cells (IECs) and an <em>in-vivo</em> 2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced CD rat model were constructed to explore the effect of EREG on CD symptoms and the underlying mechanisms.</div></div><div><h3>Results</h3><div>EREG was highly expressed in both CD colon tissues and MAT. Overexpression of EREG in adipocytes facilitated the production of inflammatory factors and lipid metabolism, as well as promoted inflammation and fibrosis in co-cultured IECs. <em>In vivo</em>, EREG knockdown effectively alleviated CD symptoms and fibrosis in TNBS-induced CD rats. The underlying mechanism may be mediated by EREG, promoting epithelial-mesenchymal transition (EMT) and the PPARγ signaling pathways in IECs. Inflammatory cytokines TNF-α and IL-17A induced EREG expression in adipocytes from CD patients</div></div><div><h3>Conclusion</h3><div>The abnormal upregulation of EREG in adipocytes within MAT contributes to the pathogenesis of CD by promoting inflammation and fibrosis. Targeting EREG may offer a novel therapeutic approach for the clinical treatment of CD.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"284 ","pages":"Pages 38-49"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-11-04DOI: 10.1016/j.trsl.2025.11.001
Henrik Christian Bidstrup Leffers , Anne Troldborg , Martin Andersen , Ana Cristina Gonzalez Sanchez , Ingileif Jonsdottir , Lina Marcela Diaz-Gallo , Saedis Saevarsdottir , Bent Deleuran , Anne Voss , Lene Dreyer , Dag Leonard , Elisabet Svenungsson , Salome Kristensen , Ada Colic , Karina Banasik , Asta Linauskas , Ole Birger Pedersen , Laura Johnsen , Niels Steen Krogh , Sisse Rye Ostrowski , Søren Jacobsen
Introduction
Understanding the associations between genetic markers, serological subsets and clinical manifestations in patients with Systemic lupus erythematosus (SLE) may elucidate disease mechanisms and inform personalised treatment strategies. This study aimed to classify SLE patients into distinct subsets based on autoantibody profiles and to examine associations with clinical and genetic characteristics, focusing on key risk loci.
Methods
A cohort of 846 SLE patients from the Danish SLE Gene-Environment Interaction study (SLE-GEIST) was analysed. Patients were grouped by cluster analysis of cumulative history of autoantibody positivity, and genotyped for known risk alleles, including HLA and non-HLA variants. Multinomial, multivariable logistic regression models were employed to identify associations between autoantibody subsets, clinical manifestations, and genetic markers.
Results
Six serological subsets with distinct characteristics were identified. The NCF2 variant was significantly associated with the subset characterised by antiphospholipid antibodies, showing an odds ratio (OR) of 2.42 (95% confidence interval [CI] 1.24–4.74) for co-positivity of anti-cardiolipin IgG and anti-beta2-glycoprotein IgG. This subset also demonstrated a higher prevalence of thrombocytopenia (OR 2.16, 95% CI 1.41–3.29). The DRB3-DQB2 haplotype exhibited a strong association with anti-SSB positivity (OR 4.85, 95% CI 2.57–9.5) and was inversely related to lupus nephritis (OR 0.57, 95% CI 0.34–0.95).
Conclusions
This study shows how the clinical and serological complexity of SLE is associated with the genetic diversity of HLA and non-HLA regions. We thus suggest further investigation of mechanistic correlates to variations in the NCF2 gene as well as the tight association between DRB3-DQB2 haplotype and anti-SSB production.
简介：了解系统性红斑狼疮（SLE）患者的遗传标记、血清学亚群和临床表现之间的关系，可能有助于阐明疾病机制，并为个性化治疗策略提供信息。本研究旨在根据自身抗体谱将SLE患者分为不同的亚群，并研究其与临床和遗传特征的关联，重点关注关键风险位点。方法：对来自丹麦SLE基因-环境相互作用研究（SLE- geist）的846例SLE患者进行队列分析。通过自身抗体阳性累积史的聚类分析对患者进行分组，并对已知的危险等位基因进行基因分型，包括HLA和非HLA变异。采用多项、多变量logistic回归模型来确定自身抗体亚群、临床表现和遗传标记之间的关联。结果：鉴定出6个具有不同特征的血清学亚群。NCF2变异与以抗磷脂抗体为特征的亚群显著相关，抗心磷脂IgG和抗β -糖蛋白IgG共阳性的比值比（OR）为2.42（95%可信区间[CI] 1.24-4.74）。该亚群还显示出较高的血小板减少率（OR 2.16, 95% CI 1.41-3.29）。DRB3-DQB2单倍型与抗ssb阳性呈强相关（OR 4.85, 95% CI 2.57-9.5），与狼疮性肾炎呈负相关（OR 0.57, 95% CI 0.34-0.95）。结论：本研究显示SLE的临床和血清学复杂性与HLA和非HLA区域的遗传多样性有关。因此，我们建议进一步研究NCF2基因变异的机制，以及DRB3-DQB2单倍型与抗ssb产生之间的密切联系。
{"title":"Autoantibody-defined subsets of patients with systemic lupus erythematosus associate with clinical manifestations, NCF2, and HLA DR3-DQ2 genotypes","authors":"Henrik Christian Bidstrup Leffers , Anne Troldborg , Martin Andersen , Ana Cristina Gonzalez Sanchez , Ingileif Jonsdottir , Lina Marcela Diaz-Gallo , Saedis Saevarsdottir , Bent Deleuran , Anne Voss , Lene Dreyer , Dag Leonard , Elisabet Svenungsson , Salome Kristensen , Ada Colic , Karina Banasik , Asta Linauskas , Ole Birger Pedersen , Laura Johnsen , Niels Steen Krogh , Sisse Rye Ostrowski , Søren Jacobsen","doi":"10.1016/j.trsl.2025.11.001","DOIUrl":"10.1016/j.trsl.2025.11.001","url":null,"abstract":"<div><h3>Introduction</h3><div>Understanding the associations between genetic markers, serological subsets and clinical manifestations in patients with Systemic lupus erythematosus (SLE) may elucidate disease mechanisms and inform personalised treatment strategies. This study aimed to classify SLE patients into distinct subsets based on autoantibody profiles and to examine associations with clinical and genetic characteristics, focusing on key risk loci.</div></div><div><h3>Methods</h3><div>A cohort of 846 SLE patients from the Danish SLE Gene-Environment Interaction study (SLE-GEIST) was analysed. Patients were grouped by cluster analysis of cumulative history of autoantibody positivity, and genotyped for known risk alleles, including HLA and non-HLA variants. Multinomial, multivariable logistic regression models were employed to identify associations between autoantibody subsets, clinical manifestations, and genetic markers.</div></div><div><h3>Results</h3><div>Six serological subsets with distinct characteristics were identified. The <em>NCF2</em> variant was significantly associated with the subset characterised by antiphospholipid antibodies, showing an odds ratio (OR) of 2.42 (95% confidence interval [CI] 1.24–4.74) for co-positivity of anti-cardiolipin IgG and anti-beta2-glycoprotein IgG. This subset also demonstrated a higher prevalence of thrombocytopenia (OR 2.16, 95% CI 1.41–3.29). The <em>DRB3-DQB2</em> haplotype exhibited a strong association with anti-SSB positivity (OR 4.85, 95% CI 2.57–9.5) and was inversely related to lupus nephritis (OR 0.57, 95% CI 0.34–0.95).</div></div><div><h3>Conclusions</h3><div>This study shows how the clinical and serological complexity of SLE is associated with the genetic diversity of HLA and non-HLA regions. We thus suggest further investigation of mechanistic correlates to variations in the <em>NCF2</em> gene as well as the tight association between <em>DRB3-DQB2</em> haplotype and anti-SSB production.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"284 ","pages":"Pages 29-37"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-11-11DOI: 10.1016/j.trsl.2025.11.002
Songyuan Yang , Zehua Ye , Sheng Zhao , Fan Cheng
Acute kidney injury (AKI) represents a significant public health challenge, marked by high rates of incidence and mortality. PANoptosis, a multifaceted process of cell death, involves complex interactions between pyroptosis, apoptosis, and necroptosis. This mechanism mediates cell death via the PANoptosome complex, which combines components from multiple cell death pathways. The therapeutic potential of targeting PANoptosis for AKI treatment is increasingly promising. In this review, we explore recent progress in the understanding of PANoptosis in AKI and examine possible therapeutic targets.
{"title":"Unraveling PANoptosis a key player in acute kidney injury and its clinical implications","authors":"Songyuan Yang , Zehua Ye , Sheng Zhao , Fan Cheng","doi":"10.1016/j.trsl.2025.11.002","DOIUrl":"10.1016/j.trsl.2025.11.002","url":null,"abstract":"<div><div>Acute kidney injury (AKI) represents a significant public health challenge, marked by high rates of incidence and mortality. PANoptosis, a multifaceted process of cell death, involves complex interactions between pyroptosis, apoptosis, and necroptosis. This mechanism mediates cell death via the PANoptosome complex, which combines components from multiple cell death pathways. The therapeutic potential of targeting PANoptosis for AKI treatment is increasingly promising. In this review, we explore recent progress in the understanding of PANoptosis in AKI and examine possible therapeutic targets.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"284 ","pages":"Pages 50-56"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-10-05DOI: 10.1016/j.trsl.2025.09.004
Jorge Gallego-Valle , Verónica Astrid Pérez-Fernández , Ana Pita , Jesús Rosales-Magallares , Rocío López-Esteban , Sergio Gil-Manso , Diego Carbonell , Ramón Pérez-Caballero , Carlos Pardo , Juan-Miguel Gil-Jaurena , Rafael Correa-Rocha , Marjorie Pion
Hyperinflammatory diseases arise from excessive immune activation, causing tissue damage and systemic inflammation. Regulatory T (Treg) cells play a key role in maintaining immune homeostasis, but their function or numbers may be impaired in pathological conditions. Conventional immunosuppressive therapies often fail to restore immune balance and are associated with significant adverse effects. An emerging therapeutic strategy involves the use of chimeric antigen receptor (CAR)-engineered Tregs to suppress aberrant immune responses. However, antigen-specific CAR-Tregs may be insufficient due to the heterogeneity of inflammatory diseases. Universal CAR-Tregs (UniCAR-Tregs), which may recognize broad immune markers, represent a more flexible and potentially effective alternative. In this study, second- and third-generation UniCAR constructs containing a monomeric streptavidin extracellular domain were introduced into human thymus-derived Tregs (thyTregs) via lentiviral transduction. The phenotype and transcriptomic profile of engineered thyTregs were characterized and compared to unmodified controls. Their suppressive capacity was assessed in vitro using a mixed lymphocyte reaction with a biotinylated intermediary, followed by evaluation in a preclinical graft-versus-host disease (GvHD) mouse model. CARs incorporating CD28 co-stimulation resulted in non-specific activation or failed to enhance suppression. In contrast, the UniCAR41BB construct more specifically activated thyTregs and augmented their suppressive function. In vivo, UniCAR41BB thyTregs delayed GvHD onset and improved survival. This study demonstrates, for the first time, that thyTregs can be effectively transduced without compromising their regulatory phenotype. Furthermore, second-generation UniCAR41BB construct enhances antigen-dependent suppressive function, highlighting its potential as a versatile therapeutic platform for GvHD and other inflammatory disorders
{"title":"Enhancing specific thymic Treg activation and function with 4-1BB monomeric streptavidin-based CARs","authors":"Jorge Gallego-Valle , Verónica Astrid Pérez-Fernández , Ana Pita , Jesús Rosales-Magallares , Rocío López-Esteban , Sergio Gil-Manso , Diego Carbonell , Ramón Pérez-Caballero , Carlos Pardo , Juan-Miguel Gil-Jaurena , Rafael Correa-Rocha , Marjorie Pion","doi":"10.1016/j.trsl.2025.09.004","DOIUrl":"10.1016/j.trsl.2025.09.004","url":null,"abstract":"<div><div>Hyperinflammatory diseases arise from excessive immune activation, causing tissue damage and systemic inflammation. Regulatory T (Treg) cells play a key role in maintaining immune homeostasis, but their function or numbers may be impaired in pathological conditions. Conventional immunosuppressive therapies often fail to restore immune balance and are associated with significant adverse effects. An emerging therapeutic strategy involves the use of chimeric antigen receptor (CAR)-engineered Tregs to suppress aberrant immune responses. However, antigen-specific CAR-Tregs may be insufficient due to the heterogeneity of inflammatory diseases. Universal CAR-Tregs (UniCAR-Tregs), which may recognize broad immune markers, represent a more flexible and potentially effective alternative. In this study, second- and third-generation UniCAR constructs containing a monomeric streptavidin extracellular domain were introduced into human thymus-derived Tregs (thyTregs) via lentiviral transduction. The phenotype and transcriptomic profile of engineered thyTregs were characterized and compared to unmodified controls. Their suppressive capacity was assessed in vitro using a mixed lymphocyte reaction with a biotinylated intermediary, followed by evaluation in a preclinical graft-versus-host disease (GvHD) mouse model. CARs incorporating CD28 co-stimulation resulted in non-specific activation or failed to enhance suppression. In contrast, the UniCAR41BB construct more specifically activated thyTregs and augmented their suppressive function. In vivo, UniCAR41BB thyTregs delayed GvHD onset and improved survival. This study demonstrates, for the first time, that thyTregs can be effectively transduced without compromising their regulatory phenotype. Furthermore, second-generation UniCAR41BB construct enhances antigen-dependent suppressive function, highlighting its potential as a versatile therapeutic platform for GvHD and other inflammatory disorders</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"284 ","pages":"Pages 1-16"},"PeriodicalIF":5.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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