Clinical and Translational Medicine最新文献

{"title":"DNA methylation profiles reveals STAB1-mediated endothelial cell and immune cell interactions in Moyamoya disease","authors":"Shihao He, Zhenyu Zhou, Rui Liang, Chengxu Lei, Yutong Liu, Jialong Yuan, Youjia Tang, Yuanli Zhao","doi":"10.1002/ctm2.70367","DOIUrl":"https://doi.org/10.1002/ctm2.70367","url":null,"abstract":"<p>Dear editor</p><p>This investigation provides a detailed characterisation of the multifaceted pathological processes driven by DNA methylation in Moyamoya disease (MMD). The Stabilin-1 (STAB1)-mediated interaction between endothelial and immune cells modulates vascular homeostasis, potentially contributing to MMD pathogenesis.</p><p>MMD is a chronic cerebrovascular disease which is characterised with distal stenosis of internal carotid artery.<span><sup>1</sup></span> Yet the marked clinical heterogeneity of Moyamoya disease suggests that genetic variants alone are insufficient to explain its pathogenesis, underscoring the need to interrogate complementary epigenetic mechanisms such as DNA methylation. Sung et al. employed the Illumina 450K array on a small cohort of endothelial cells and validated their findings in a HUVEC tube formation assay, revealing overexpressed Sort1's role in MMD angiogenesis.<span><sup>2</sup></span> However, their limited sample size and exclusive focus on endothelial cells constrain the generalisability of these results, underscoring the need for broader investigation. Tokairin et al. used the Illumina 850 K to conduct genome-wide DNA methylation in female cohorts. In MMD, hypomethylation was observed in genes regulating natural killer cell signalling, cell growth and migration, DNA methylation and so on.<span><sup>3</sup></span> The study did not stratify by clinical subtype, lacked male participants, and provided no functional validation. In contrast, the current work employs a balanced, subtype-defined discovery set, couples methylome data with intracranial RNA-seq, and experimentally demonstrates that STAB1 hypomethylation enhances endothelial ECM production and tube formation. These additions not only corroborate Tokairin's immune-inflammatory theme but also position STAB1 as a mechanistic link between aberrant immunity and intimal thickening in Moyamoya disease.</p><p>In the discovery cohort, we enrolled 30 participants, comprising 10 with haemorrhagic (HEM) and 10 with ischemic (IS) Moyamoya disease, alongside 10 healthy controls (HC). We mapped the DNA methylation profiles of ischemic and haemorrhagic Moyamoya disease patients via the Illumina 850K chip (Figure S1). The middle cerebral artery (MCA) sequencing data of 11 MMD patients and 9 control patients from GSE157628 were used as the validation cohort. Through weighted gene co-expression network analysis (WGCNA) and differential analysis of the discovery cohort and the validation cohort, the most potential biomarker, STAB1, was obtained (Figures S1, S2 and 1A).</p><p>The extracellular matrix (ECM) is a macromolecular reticular structure synthesised and secreted by cells to the extracellular space. Matsuo et al. conducted immunohistochemical analysis on the specimens of the middle cerebral arteries (MCA) from autopsies of MMD patients and found that ECM was significantly accumulated in the thickened intima.<span><sup>4</sup></span> The ECM components (fib","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70367","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coordination of SLC39A1 and DRP1 facilitates HCC recurrence by impairing mitochondrial quality control","authors":"Rui Li, Zhe Wang, Lixin Cheng, Zhiqiang Cheng, Qiong Wu, Fengjuan Chen, Dong Ji, Qingxian Cai, Yijin Wang","doi":"10.1002/ctm2.70362","DOIUrl":"https://doi.org/10.1002/ctm2.70362","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Despite rapid advances in HCC therapy, surgical resection is still the most effective treatment. However, postoperative relapse develops in a large population and the mechanism remains to be explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>HCC resection samples were retrospectively collected from 12 nonrelapsed and 15 relapsed HCC patients for RNA sequencing. Liver-specific solute carrier family 39 member 1 (SLC39A1) knockout mice were generated by crossing Alb-Cre mice and SLC39A1<sup>flox/flox</sup> mice. Liver samples were examined for inflammation, fibrosis, proliferation, and apoptosis. Mitochondrial mass, autophagy, ROS, and mitochondrial membrane potential (MMP), were detected. Co-immunoprecipitation and molecular docking were used to identify protein interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SLC39A1 is highly expressed in relapsed HCC patients and negatively correlated with overall survival. Knockdown of SLC39A1 inhibited cell proliferation by arresting the cell cycle and promoted cell apoptosis, accompanied by suppressing autophagic flux. Mechanistically, SLC39A1 interacts with a member of the dynamin superfamily of GTPases dynamin-related protein 1 (DRP1), followed by facilitating mitochondrial fission and MMP reduction. Inhibition of DRP1 abolished SLC39A1-induced mitochondrial division and MMP depolarization, while overexpression of DRP1 reversed mitochondrial fusion and MMP hyperpolarization in SLC39A1 silenced cells, accompanied by recuperative cell proliferative ability. SLC39A1<sup>flox/flox</sup>,Alb-Cre mice displayed fewer tumour numbers and less liver damage compared with SLC39A1<sup>flox/flox</sup> mice. A specific peptide targeting SLC39A1 to disturb the combination of full-length SLC39A1 and DRP1 efficiently suppressed HCC progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings reveal a key role of SLC39A1-DRP1 interaction in HCC progression by disturbing mitochondrial quality control and providing a competitive peptide as a potential anti-tumour therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>SLC39A1 correlates with HCC recurrence and HCC mortality.</li>\u0000 \u0000 <li>Interaction of SLC39A1 and DRP1 facilitates HCC by regulating mitochondrial quality control.</li>\u0000 \u0000 <li>Specific peptide ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70362","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevation of ISG15 promotes diabetic kidney disease by modulating renal tubular epithelial cell pyroptosis","authors":"Lingzhi Huang, Xinyi Chen, Yawen Shao, Shujun Deng, Chen Wang, Jianqiao Chen, Yongsheng Xie, Siming Yuan, Liqin Tang","doi":"10.1002/ctm2.70337","DOIUrl":"https://doi.org/10.1002/ctm2.70337","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Fibrosis and inflammation in the renal tubular epithelial cells (TECs) are key contributors to the pathology of diabetic kidney disease (DKD). Nevertheless, the precise triggers of these processes remain unclear. This study aimed to explore the role of interferon-stimulated gene 15 (ISG15) in the injury of TECs induced by high glucose (HG) conditions and its implications for the development of DKD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>ISG15 knockout (ISG15 KO) mice injected with streptozotocin-treated mice on a high-fat diet were used to investigate its role in DKD. Cellular models with ISG15 knockdown were exposed to HG conditions to assess the effects of ISG15 on cellular responses. Subsequently, we evaluated the impact of ISG15 on pyroptosis, a form of programmed cell death, to understand its potential role in DKD pathology. Furthermore, RNA sequencing (RNA-seq) and molecular biology techniques were employed to explore the signalling pathways potentially regulated by ISG15.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We first confirmed an up-regulation of ISG15 within the renal tubule in DKD. The deletion of ISG15 alleviated renal functional damage, fibrosis and inflammation, which correlated with reduced ISGylation levels. Mechanistic investigation revealed that HG stimulation in TECs disrupted the mtDNA–cGAS–STING signalling, which exacerbates the DKD through the NLRP3–CASP1–GSDMD axis. Furthermore, we uncovered a bidirectional regulatory loop between STING and ISG15, with STING enhancing ISG15 expression upstream and ISG15 modulating STING expression through ISGylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>ISG15–mtDNA–STING emerges as a critical hub that integrates the processes of pyroptosis, fibrosis and inflammation. Therapeutic interventions that target this signalling network at various levels may pave the way for innovative treatments for DKD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>ISG15 is highly expressed in both DKD mice and renal tubular epithelial cell cultured in HG condition.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>ISG15 promotes DKD pyroptosis via NLRP3–CASP1–GSDMD axis.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>ISG15–mtDNA–STING ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The deubiquitinase OTUD3 plays a neuroprotective role by reducing ferroptosis induced by cerebral ischaemia reperfusion via stabilizing PLK1 via deubiquitination","authors":"Jing Cheng, Qi Tian, Hao-Ran Lu, Hong-Xiang Jiang, Xiao-Hong Qin, Yan-Qin Fan, Zhi-Biao Chen, Li-Quan Wu","doi":"10.1002/ctm2.70347","DOIUrl":"https://doi.org/10.1002/ctm2.70347","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Ischaemic stroke is one of the most common serious diseases observed in elderly people, which is caused by ischaemia-reperfusion (I/R) injury. Ovarian tumour domain-containing protein 3 (OTUD3) is a member of the ovarian tumour proteases (OTUs) family of deubiquitination enzymes located in the cytoplasm. We previously showed that the expression of OTUD3 in neurons was significantly reduced after cerebral I/R in mice. In addition, OTUD3 knockdown aggravated ferroptosis and brain damage following I/R in mice, and overexpression of OTUD3 reduced the mortality of cortical neurons in an oxygen glucose deprivation model (OGD/R). Co-immunoprecipitation-mass spectrometry analysis revealed that OTUD3 could bind to the amino acid sequence 35–305 of PLK1. Single-cell sequencing results suggested that PLK1 expression was significantly reduced in mouse neurons after I/R injury. Similarly, reduced PLK1 expression was found in the cortical brain tissues of I/R mice and in the OGD/R-stimulated primary cortical neurons of mice. In vitro experiments showed that OTUD3 overexpression led to the upregulation of PLK1 expression, and inhibition of PLK1 suppressed the inhibitory effect of OTUD3 overexpression on ferroptosis. Moreover, PLK1 positively regulated the PI3K/AKT signalling pathway in neurons after I/R injury, and inhibition of PI3K activity suppressed the inhibitory effect of PLK1 on ferroptosis. Ubiquitination experiments showed that OTUD3 modified PLK1 through deubiquitinating K48-linked ubiquitination, thereby reducing its degradation by ubiquitination and stabilizing PLK1 expression. These results indicated that OTUD3 could upregulate PLK1 through deubiquitination modification, thereby activating the PI3K/AKT signalling pathway and reducing ferroptosis after cerebral I/R. Animal behavioural experiments and cellular methyl thiazolyl tetrazolium and lactate dehydrogenase experiments revealed that inhibition of PLK1 exacerbated brain damage after I/R in mice. Inhibition of OTUD3 deubiquitination enzyme activity attenuated the neuroprotective effect of OTUD3. In conclusion, our findings provide evidence that OTUD3 reduces ferroptosis by upregulating PLK1 expression through deubiquitination modification and exerts neuroprotective effects in cerebral I/R injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>For the first time, it has been clarified that OTUD3 exerts neuroprotective effects in cerebral ischemia/reperfusion injury by deubiquitinating PLK1 to regulate the PI3K/AKT pathway and inhibit ferroptosis.</li>\u0000 \u0000 <li>The study first demonstrates that OTUD3 binds to the amino acid residues 35305 of PLK1 and deubiquitinates PLK1 (targeting K48-linked ubiquit","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblasts-specific p16INK4a exacerbates inflammageing-mediated post-infarction ventricular remodelling through interacting with STAT3 to regulate NLRP3 transcription","authors":"Xin Gu, Yingqiang Du, Jin'ge Zhang, Jiyu Li, Haiyun Chen, Yujie Lin, Yue Wang, Chunli Zhang, Shiyu Lin, Nannan Hao, Chengyi Peng, Jiacheng Ge, Jin Liu, Yan Liang, Yongjie Zhang, Xiaoyan Wang, Fang Wang, Jianliang Jin","doi":"10.1002/ctm2.70344","DOIUrl":"https://doi.org/10.1002/ctm2.70344","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Inflammageing represents both a critical pathophysiological hallmark and independent risk factor for myocardial infarction (MI), with age-related increases observed in MI incidence and severity of post-MI ventricular remodelling. Novel therapeutic strategies targeting inflammageing-driven mechanisms are urgently required to attenuate adverse ventricular remodelling following MI. This investigation was designed to elucidate the impact of fibroblast-specific <i>p16</i><i><sup>INK4a</sup></i> on inflammageing-associated ventricular remodelling after MI and to develop a targeted nanotherapy to mitigate this process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>We found that p16-mediated inflammageing positively correlated with the severity of post-infarction ventricular remodelling in patients. <i>POSTN</i>-driven <i>p16<sup>INK4a</sup></i> knockout improved cardiac function, and reduced ventricular remodelling, myocardial inflammation and NLRP3 signalling activation following MI through downregulating STAT3-mediated NLRP3 inflammasome and upregulating glutathione metabolism pathway in fibroblasts. <i>P16<sup>INK4a</sup></i> overexpression induced NLRP3 signalling activation through upregulating <i>NLRP3</i> transcribed by STAT3 in fibroblasts. In terms of mechanisms, p16<sup>INK4a</sup> interacted with STAT3, which depended on the SH2 domain of STAT3; <i>P16<sup>INK4a</sup></i> promoted the interaction of EZH2 and STAT3, increased the di-methylation on K49 and phosphorylation on Y705 of STAT3 by EZH2, and promoted <i>NLRP3</i> transcription through regulating histone modification in the <i>NLRP3</i> promoter by interfering the formation of Bmi-1-EZH2 or Bmi-1-BCL6 complex in fibroblasts. Injection of p16<sup>INK4a</sup>-accumulated ageing cardiac fibroblasts, or <i>p16<sup>INK4a</sup></i> overexpression adenovirus aggravated profibrosis and proinflammation in MI area. However, a novel FH peptide ‘FHKHKSPALSPV’-neutrophil membrane proteins (NMPs)-artificial lipid (Li) membranes-mesoporous silica nanoparticle (MSN) core (FNLM)-nanocaged <i>p16<sup>INK4a</sup></i>-siRNA, as a newly constructed nanomaterial drug, could prevent post-infarction ventricular remodelling through inhibiting <i>NLRP3</i> transcription in targeted cardiac fibroblasts and ameliorating proinflammation and profibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>P16<sup>INK4a</sup> drives inflammageing-mediated post-MI ventricular remodeling by activating STAT3/NLRP3 signaling in fibroblasts. Targeting <i>p16<sup>INK4a</sup></i> via FNLM-siRNA nanotherapy represents a novel strategy to ameliorate adverse cardiac rem","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 6","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Responsiveness of different MET tumour alterations to type I and type II MET inhibitors","authors":"Yonina R. Murciano-Goroff, Valentina Foglizzo, Jason Chang, Natasha Rekhtman, Ann Elizabeth Sisk, Jamie Gibson, Lia Judka, Kristen Clemens, Paola Roa, Shaza Sayed Ahmed, Nicole V. Bremer, Courtney Lynn Binaco, Sherifah Kemigisha Muzungu, Estelamari Rodriguez, Madeline Merrill, Erica Sgroe, Matteo Repetto, Zsofia K. Stadler, Michael F. Berger, Helena A. Yu, Eneda Toska, Srinivasaraghavan Kannan, Chandra S. Verma, Alexander Drilon, Emiliano Cocco","doi":"10.1002/ctm2.70338","DOIUrl":"https://doi.org/10.1002/ctm2.70338","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mutations in c-MET receptor tyrosine kinase (MET) can be primary oncogenic drivers of multiple tumour types or can be acquired as mechanisms of resistance to therapy. MET tyrosine kinase inhibitors (TKIs) are classified as type I or type II inhibitors, with the former binding to the DFG-in, active conformation of MET, and the latter to the DFG-out, inactive conformation of MET. Understanding how the different classes of MET TKIs impact tumours with varied MET alterations is critical to optimising treatment for patients with MET altered cancers. Here, we characterise MET mutations identified in patients’ tumours and assess responsiveness to type I and II TKIs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used structural modelling, in vitro kinase and in cell-based assays to assess the response of MET mutations to type I and II TKIs. We then translated our pre-clinical findings and treated patients with MET mutant tumours with selected inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (MET<sup>G1090A</sup>, MET<sup>D1213H</sup>, MET<sup>R1227K</sup> and a MET<sup>Y1230S</sup>) in samples from patients with multiple solid tumours, including patients who had been previously treated with type I inhibitors.</p>\u0000 \u0000 <p>In silico modelling and biochemical assays across a variety of MET alterations, including the uncharacterised MET<sup>G1090A</sup> and the MET<sup>Y1230S</sup> substitutions, demonstrated impaired binding of type I but not of type II TKIs (i.e., cabozantinib/foretinib). Applying our pre-clinical findings, we then treated two patients (one with a non-small-cell lung cancer and one with a renal cell carcinoma) whose tumours harboured these previously uncharacterised MET alterations with cabozantinib, a type II MET TKI, and observed clinical responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Comprehensive characterisation of the sensitivity of mutations to different TKI classes in oncogenic kinases may guide clinical intervention and overcome resistance to targeted therapies in selected cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Kinase mutations in RTKs are primary or secondary drivers in multiple cancer types</li>\u0000 \u0000 <li>Some","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the bench-to-bedside divide in microbiome research","authors":"Sondra Turjeman, Omry Koren","doi":"10.1002/ctm2.70358","DOIUrl":"https://doi.org/10.1002/ctm2.70358","url":null,"abstract":"<p>Microbiome research has expanded rapidly in recent years, producing a large volume of publications across many clinical fields. However, despite the numerous studies reporting correlations between microbial dysbiosis and host health and disease states,<span><sup>1, 2</sup></span> few findings have translated into interventions that impact clinical care. For many healthcare professionals, this gap between discovery and application has become a clear call to action, underscoring the need for new translational strategies that bridge basic science and clinical relevance.<span><sup>3</sup></span></p><p>In a recent <i>Cell</i> perspective,<span><sup>4</sup></span> we and our co-authors proposed a structured, iterative approach to improve microbiome translation from early discovery studies through to clinical trials (Figure 1). While this framework emphasises experimental models and data integration, its success ultimately depends on multidisciplinary collaboration between clinicians and researchers. Broader progress in microbiome translation will depend on better integration of clinical insight with experimental design; identifying meaningful cross-species phenotypes, defining clinically relevant endpoints, and co-developing translational models will be key to making microbiome science more clinically actionable.</p><p>Many research questions in microbiome science begin with clinical observations of variability in patient response, symptom clustering, or disease trajectories that do not follow expected patterns. When these insights are systematically recorded and paired with biological sampling, they become a foundation for hypothesis generation.</p><p>Specifically, the growing availability of large, deeply phenotyped cohorts allows for exploration of clinical questions at scale. By combining rich clinical metadata with microbiome and metabolome profiling, researchers can build large, diverse databases, so-called ‘meta-cohorts’, which can be leveraged to reveal robust and reproducible associations between a variety of host states and multi-omics profiles.<span><sup>5</sup></span> Statistical modelling and machine learning approaches can then be used to identify conserved microbial signatures, host–microbe interactions or functional pathways associated with specific clinical phenotypes<span><sup>6</sup></span> which can then be examined mechanistically to better understand disease aetiology and define biomarkers for diagnosis or therapeutic intervention.</p><p>Once robust associations are identified through clinical observations and large-scale data analysis, the next step is to determine whether these patterns reflect causal relationships. Experimental models, ranging from in vitro gut culture systems<span><sup>7</sup></span> to gnotobiotic animals<span><sup>8</sup></span>, allow researchers to examine how specific microbial strains, functions, or metabolites influence host physiology or disease progression. Proof-of-concept studies often begin with","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PICH deficiency attenuates the progression of lung adenocarcinoma and disrupts the DNA damage response","authors":"Li Miao, Lu Weina, Lou Jiafei, Chen Gaoying, Yu Yinghui, Wu Yinfang, Li Fei, Zhang Chao, Tang Haoyu, Weng Qingyu, Zheng Kua, Gao Shenwei, Wu Yanping, Zhu Chen, Zhang Min, Yu Fangyi, Jin Rui, Chen Zhihua, Geng Xinwei, Ying Songmin, Li Wen","doi":"10.1002/ctm2.70349","DOIUrl":"https://doi.org/10.1002/ctm2.70349","url":null,"abstract":"<p>Dear Editor,</p><p>In this study, we showed that the DNA helicase PICH is essential for the progression of <i>Kras<sup>G12D</sup></i>-driven lung adenocarcinoma in vivo and for the growth of human lung adenocarcinoma cells in vitro. These findings suggest that PICH might be a promising therapeutic target in lung adenocarcinoma.</p><p>Chromosomal instability is widely recognised as a hallmark of cancer.<span><sup>1</sup></span> Disrupting pathways that regulate chromosomal stability offers a potential strategy for cancer therapy. Lung cancer is the leading cause of cancer-related death worldwide.<span><sup>2</sup></span> Lung cancer patients, particularly those with advanced disease, still face a poor prognosis and a dearth of effective treatment strategies. PICH, a member of the SNF2 family of ATPases, is critical for maintaining chromosomal stability by facilitating mitotic chromosome organisation and segregation.<span><sup>3</sup></span> Recently, several studies support the notion that PICH is essential for the proliferation of certain cancer cell types and is associated with unfavourable prognoses in cancer patients.<span><sup>4, 5</sup></span> However, the precise role of PICH in lung cancer remains largely undefined due to the limited availability of compelling preclinical evidence, particularly from in vivo primary tumour models. To bridge this gap, we systematically examined the role of PICH in lung cancer through clinical analysis, in vitro experiments, and in vivo primary tumour model to thoroughly examine PICH's involvement in lung cancer and evaluate its potential for therapeutic intervention.</p><p>To investigate the expression pattern of PICH in lung cancer, we first analysed publicly available datasets, focusing specifically on the two most common subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).<span><sup>6-8</sup></span> Elevated expression of PICH at both the mRNA and protein levels was observed in LUAD and LUSC tissues (Figures 1A–C and S1A–C). To validate these results, immunohistochemical analysis was performed on 25 paired tumour and adjacent normal lung tissues from LUAD patients, revealing a notable upregulation of PICH in tumour tissues (Figure 1D and E). Additionally, higher PICH expression levels were associated with advanced tumour stages (Figure S2). Next, the prognostic value of PICH in lung cancer patients was evaluated. PICH expression was higher in LUAD patients who died within 3 years of diagnosis compared to those who survived (Figure 1F). In line with these findings, analysis of publicly available datasets revealed that high levels of PICH predicted worse clinical outcomes across multiple survival indicators in LUAD—including overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), progression-free interval (PFI), first progression (FP), and relapse-free survival (RFS)—but not in LUSC (Figures 1G–L and S1D–I).</p><p>A more detailed subgroup analysis dem","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of HMOX1 by mesenchymal stem cell cytotherapy inhibits osteoclastogenesis and myeloma-induced bone disease","authors":"Xin Li, Wen Ling, Bart Barlogie, Shmuel Yaccoby","doi":"10.1002/ctm2.70302","DOIUrl":"https://doi.org/10.1002/ctm2.70302","url":null,"abstract":"<p>Dear Editor,</p><p>Multiple myeloma (MM) cells typically grow in focal lesions (FLs), which often turn into osteolytic lesions.<span><sup>1</sup></span> Through the study of cytotherapy with mesenchymal stem cells (MSCs) for treating MM, we discovered that MSCs mediate HMOX1 expression in monocytes to balance differentiation of osteoclast precursors into osteoclasts. Lower expression of HMOX1 in the MM bone is associated with poor outcome and induction of HMOX1 pharmacologically resulted in suppression of MM-induced bone disease.</p><p>Previously, we showed that MM-induced osteolytic bone disease can be treated via direct cytotherapy with MSCs using our well-established SCID-hu and SCID-rab MM models<span><sup>2, 3</sup></span> (see Methods and Discussion in Supplementary Information). By applying global gene expression profiling (GEP) on the whole human bone in SCID-hu mice we found that MSC cytotherapy induced expression of several genes associated with the macrophages and monocytes (Figure 1A, Table S1). Of the top upregulated genes, we focused on <i>HMOX1</i>, which encodes heme oxygenase 1, and known as an inducible factor that mediate oxidative stress, inflammation and bone remodelling.<span><sup>4</sup></span> <i>HMOX1</i> expression in bone was consistently upregulated following MSC cytotherapy in bones engrafted with 4 different MM cell lines (Figure 1B and C). Immunohistochemistry post-cytotherapy revealed induction of HMOX1 protein in monocytes and macrophages and some MM cells (Figure 1D). <i>HMOX1</i> expression is highest among immune cells in MM bone marrow based on publicly available scRNA-seq data (Figure 1E–G).</p><p>To study whether MSCs mediate osteoclastogenesis through HMOX1, we co-cultured MSCs with osteoclast precursors (pOC) and found that MSCs suppressed their differentiation into multinucleated osteoclasts, an effect that was associated with upregulation of HMOX1 at the RNA and protein levels, lower expression of the osteoclast markers: <i>ACP5</i> (TRAP), <i>CTSK</i>, and <i>VTNR</i>, and lower secretion of HMGB1 (Figure 2A–G). RANKL is a master regulator of osteoclastogenesis that acts on pOC via <i>TNFRSF11A</i>/RANK. Using qRT-PCR, immunofluorescence and immunoblot we found that MSCs conditioned medium reduced <i>TNFRSF11</i> expression and RANK levels in pOC (Figure 2H–J). MSCs secreted factors that restrain osteoclastogenesis are discussed in Supplementary Information.</p><p>NFκB is induced by RANK/RANKL signalling and is a vital signalling pathway for osteoclastogenesis.<span><sup>5</sup></span> MSC-conditioned medium inhibited cytoplasmic phosphorylated IκBα and NFκB p65 and nuclear NFκB p65 in pOC (Figure 3A–C).</p><p>NFATC1 is a main downstream transcription factor activated by the RANKL/NFκB pathway in osteoclasts that induces expression of typical genes associated with osteoclasts, such as <i>CTSK</i> and <i>APC5/TRAP</i>.<span><sup>6</sup></span> Compared to pOC cultured alone, pOC cultured with MSCs had","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling T cell exhaustion through co-inhibitory receptors and its transformative role in cancer immunotherapy","authors":"Simin Xiang,&nbsp;Sen Li,&nbsp;Junfen Xu","doi":"10.1002/ctm2.70345","DOIUrl":"https://doi.org/10.1002/ctm2.70345","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Persistent stimulation from cancer antigens leads to T lymphocytes (T cells) exhaustion, with up-regulated expression of co-inhibitory receptors, including programmed death-1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These receptors collectively impair T cell function via distinct molecular pathways, contributing to immune evasion and cancer progression. This review highlights the therapeutic promise of immune checkpoint inhibitors (ICIs) in reversing T cell exhaustion while delving into the complex molecular processes and functional works of these important co-inhibitory receptors in tumourigenesis. Additionally, we examine the synergistic effects of combining ICIs with other therapeutic strategies, which can enhance anti-tumour efficacy. Finally, the clinical implications of bispecific antibodies are highlighted, representing a promising frontier in cancer immunotherapy, that could revolutionise treatment paradigms while improving patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>This review discusses five major co-inhibitory receptors (PD-1, CTLA-4, LAG-3, TIM-3 and TIGIT) and their related mechanisms of T cell exhaustion in the tumour environment.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>We also discuss the clinical application of checkpoint inhibitors (ICIs) in cancer immunotherapy.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>The potential of bispecific antibodies (BsAbs) in cancer immunotherapy is highlighted.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}