Clinical and Translational Medicine最新文献

{"title":"Spatiotemporal transcriptomics for tumour microenvironment remodelling in cancer progression and therapy","authors":"Ying Kang,&nbsp;Qinjing Wang,&nbsp;Siqi Xu,&nbsp;Jiming Guo,&nbsp;Yue Ming,&nbsp;Weixing Chen,&nbsp;Min Wang,&nbsp;Zhijie Huang,&nbsp;Yisheng Huang,&nbsp;Bo Jia","doi":"10.1002/ctm2.70858","DOIUrl":"10.1002/ctm2.70858","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Spatiotemporal transcriptomics (STT) integrates spatially resolved gene expression with temporal information derived from staged samples, paired treatment specimens, or computational inference, providing a framework for reconstructing tissue-level dynamics. In the tumour microenvironment (TME), STT extends static molecular and cellular maps by revealing how cellular neighbourhoods and functional niches are reorganised during tumour evolution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main text</h3>\u0000 \u0000 <p>This review examines how STT characterises TME remodelling during malignant transformation, invasion, metastasis, ageing, and treatment response. We discuss strategies for resolving temporal dynamics, including stage-stratified sampling, paired or serial specimens, pseudotime and trajectory inference, and complementary intravital imaging. We further consider how spatiotemporal analyses can connect changes in cellular states, spatial organisation, and intercellular interactions with clinically relevant tumour phenotypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>By linking the spatial organisation of the TME with stage- and treatment-associated molecular changes, STT may improve the prioritisation of candidate targets, treatment stratification, and the development of precision oncology strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163636","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":"A single-cell census of pulmonary endarterectomies tissue across different anatomical regions in chronic thromboembolic pulmonary hypertension","authors":"Rui Zhang,&nbsp;Yunlong Zhang,&nbsp;Huiting Li,&nbsp;Jing Zhang,&nbsp;Shou Han,&nbsp;Xinbo Cheng,&nbsp;Qinhua Zhao,&nbsp;Jing He,&nbsp;Cijun Luo,&nbsp;Hongling Qiu,&nbsp;Jianfeng Zhang,&nbsp;Sugang Gong,&nbsp;Lan Wang","doi":"10.1002/ctm2.70864","DOIUrl":"10.1002/ctm2.70864","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Pulmonary endarterectomy (PEA) remains one of potentially curative options for chronic thromboembolic pulmonary hypertension (CTEPH). The operation can remove proximal thromboembolic materials and their secondary branches. However, the cellular landscape and pathological features across different anatomical regions remain limited understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Ten patients with CTEPH undergoing PEA surgery and six reference distal pulmonary arteries were conducted single-cell transcriptomics to profile the cellular composition of the main and its bifurcate portion.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Pronounced muscularised and fibrotic thrombi organisation were presented in the main portion, and the proportion of mononuclear phagocytes was significantly increased. Inflammatory response and pro-inflammatory activity were attributed to CD8+ effector T cells and nature killer cells subsets and a M1-like (high IL1B and TNF, minimal IL6) phenotypic macrophage subcluster. The colander-like lesions were dominant in the bifurcate portion, and the percentage of plasma cells was markedly increased. Immune dysregulation was induced from CD4 naïve T cells, and a downregulation of M2-like macrophage infiltration into the vascular wall. The expression of plasminogen activator, urokinase receptor, urokinase receptor (PLAUR; plasminogen activator) were observed in M2-like (high MRC1 and CD163, virtually no IL1B or TNF) macrophage in bifurcate portion. Notably, one of smooth muscle cells (SMCs) subclusters in the bifurcate portion gained more significantly myofibroblast markers than those in the main portion, and other subclusters remained the function of SMCs.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The regions with colander-like lesions changes had more obviously T cell and macrophages driving immune-inflammatory response and SMCs differentiation, suggesting that combining therapeutic interventions after surgical removal of accessible thrombus may be beneficial.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;This study reveals the comprehensive cellular composition in main/lobar and bifurcate pulmonary endarterectomy (PEA) specimens at the single-cell level. The bifurcate regions with colander had more obviously T cell and macrophages driving immune-inflammatory response and smooth muscle cells (SMCs) d","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164766","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":"After delivery: How recipient cells shape the fate and function of transplanted mitochondria","authors":"Zhi-Yuan Zhang,&nbsp;Bo-Quan Qin,&nbsp;Shi-Zhou Wu,&nbsp;Hui Zhang","doi":"10.1002/ctm2.70857","DOIUrl":"10.1002/ctm2.70857","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondrial transplantation is built on a simple idea: failing cells might be rescued by healthy mitochondria. The approach has entered early clinical testing, and encapsulation and cell-type targeting have improved uptake in selected systems. Better delivery, however, does not explain the therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body</h3>\u0000 \u0000 <p>Internalised donor mitochondria encounter an established network, quality-control machinery and sensors for mitochondrial material. Donor material may remain in the endolysosomal system or reach the cytosol. Cytosolic fates include network integration, clearance and a candidate functional contribution without fusion. Intracellular processing may also generate bioactive cargo. These fates imply different mechanisms and evidence requirements. This Review examines how recipient cells shape the contribution of internalised mitochondria, while recognising extracellular routes to benefit. We distinguish direct transplantation evidence from mechanistic support drawn from endogenous mitochondrial biology and natural intercellular transfer. The required donor fate and duration depend on the therapeutic task. Transient rescue may rely on short-term donor function or productive processing in specific models; sustained support may depend on continued donor function, recipient adaptation or redosing. Durable mitochondrial DNA (mtDNA) correction requires donor-mtDNA retention and replication.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Linking these tasks to product design, safety assessment and clinical endpoints shifts the question from how many mitochondria enter cells to what they accomplish after arrival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Recipient-cell handling shapes what transplanted mitochondria do after uptake.</li>\u0000 \u0000 <li>Uptake, structural integration and donor mitochondrial DNA retention require distinct evidence.</li>\u0000 \u0000 <li>Transient rescue, sustained support and durable mitochondrial DNA correction impose different requirements.</li>\u0000 \u0000 <li>Therapeutic goals should guide donor selection, product testing and clinical endpoints.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166180","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":"A serum proteomics-based predictive model for steroid-resistant immune checkpoint inhibitor associated myocarditis","authors":"Yerui Zhang,&nbsp;Yihan Li,&nbsp;Jian Zhang,&nbsp;Xiaozhen He,&nbsp;Yihui Shen,&nbsp;Yuchen Xu,&nbsp;Hui Zhang,&nbsp;Jianan Pan,&nbsp;Xuejun Wang,&nbsp;Shilong Zhang,&nbsp;Yan Wang,&nbsp;Leilei Cheng","doi":"10.1002/ctm2.70843","DOIUrl":"10.1002/ctm2.70843","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immune checkpoint inhibitor–associated myocarditis (ICIAM) is one of the immune–related adverse events (irAEs) with low incidence but extremely high mortality. High–dose glucocorticoid pulse therapy remains the recommended initial treatment for patients with ICIAM. However, an inadequate response to corticosteroid therapy is observed in some patients, who are subsequently classified as having steroid-resistant immune checkpoint inhibitor-associated myocarditis (srICIAM). Early combination of second-line immunosuppression may represent an effective therapeutic strategy. However, Biomarkers capable of identifying such patients before treatment are currently lacking. We therefore sought to characterize circulating inflammatory proteins associated with corticosteroid responsiveness and to derive a preliminary serum-based prediction model for steroid-resistant ICIAM (srICIAM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Serum specimens obtained from patients with ICIAM at baseline and after methylprednisolone treatment were analyzed to quantify circulating immune-related proteins using an antibody-based proteomic assay. We developed a preliminary model for the early identification of patients at risk of srICIAM using proteins selected by three complementary machine–learning algorithms and evaluated its discriminatory performance in an internal hold-out cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Pretreatment serum samples from 47 patients with ICIAM were used to establish a protein–based prediction model, with 33 patients assigned to model development and 14 to internal validation. Patients with a high srICIAM predictive score (≥.5625) based on CXCL9, TRANCE and MMP1 were more likely to show an inadequate early response to corticosteroid therapy and may warrant closer clinical monitoring and further evaluation. The analysis also revealed that several serum immune proteins decreased in patients with ICIAM after methylprednisolone therapy. Serum CXCL9 levels were positively correlated with lactate dehydrogenase (LDH) and cardiac troponin T (cTnT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Serum immune proteins were dynamically altered in patients with ICIAM after methylprednisolone therapy. The preliminary score may enable earlier recognition of patients at risk of an inadequate corticosteroid response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104740","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":"Integrative characterization of human hepatocellular carcinoma-derived organoids and their HBV-associated biology","authors":"Seo-Hyeon Kim,&nbsp;YoungRok Choi,&nbsp;Eun Woo Choi,&nbsp;Se Hui Kim,&nbsp;Seung Cheol Oh,&nbsp;Jae Yoon Kim,&nbsp;Su young Hong,&nbsp;Suk Kyun Hong,&nbsp;Kwang-Woong Lee,&nbsp;Ja-Lok Ku","doi":"10.1002/ctm2.70853","DOIUrl":"10.1002/ctm2.70853","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and is characterized by a high degree of heterogeneity. However, HCC treatment remains difficult, highlighting the need to better define molecular subgroups of HCC and understand their potential relationships with therapeutic response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we established 20 patient-derived organoids and 12 patient-derived cell lines from 20 individuals diagnosed with HCC. These models were comprehensively characterized using whole-exome sequencing, RNA sequencing, drug screening, and hepatitis B virus (HBV)-targeting PCR with a focus on HBV-related HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Based on transcriptomic profiling, this study classified HCC into two molecular subtypes, aligning with previously reported classifications. Drug screening revealed that the greater enrichment of the PI3K/AKT/mTOR signalling pathway was associated with increased sensitivity to everolimus and lenvatinib. Integrated transcriptomic and drug-response analyses further identified candidate genes associated with lenvatinib response. In addition, polymerase chain reaction (PCR) analysis targeting the HBV surface, core, and X genes demonstrated noticeable discrepancies relative to the clinically reported HBV infection status. Notably, HBV DNA detection was associated with activation of the calcium signalling pathway and oxaliplatin response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study provides a valuable resource for investigating the biology and pharmacological characteristics of HCC, particularly in the context of molecular subtypes and HBV-associated mechanisms. Ultimately, these findings offer additional insights into HCC heterogeneity and drug response and may serve as a basis for further investigation of molecular determinants of therapeutic response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104793","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":"Toward selective amyloid clearance through rational nanomedicine design","authors":"Tianyi Qi,&nbsp;Jie Zhuang,&nbsp;Yuejuan Cao,&nbsp;Xinglu Huang","doi":"10.1002/ctm2.70859","DOIUrl":"10.1002/ctm2.70859","url":null,"abstract":"&lt;p&gt;With the accelerating global ageing population, Alzheimer's disease (AD) has emerged as a major medical challenge with profound implications for human health and society. Yet, the blood–brain barrier, complex disease pathophysiology, and lack of effective targeted interventions remain major obstacles to the treatment of AD. Accumulation of amyloid-β (Aβ) remains a defining pathological feature of AD and one of its most intensively pursued therapeutic targets. Recent clinical studies of Aβ-directed monoclonal antibodies have shown that cerebral amyloid reduction can be accompanied by a measurable slowing of clinical decline.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; At the same time, the clinical benefits of anti-Aβ therapies remain incomplete, highlighting the need to better understand how therapeutic agents engage and remodel disease-relevant Aβ assemblies. Nanomedicine offers opportunities to engineer such interactions at the molecular level, but translating these opportunities into effective therapies requires a clearer link between molecular recognition, structural intervention and therapeutic outcome.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Together, these considerations underscore the need for therapeutic strategies that can selectively engage disease-relevant Aβ assemblies and translate molecular recognition into effective amyloid remodelling in the brain.&lt;/p&gt;&lt;p&gt;To address this need, we recently developed &lt;sub&gt;Aβ3&lt;/sub&gt;FTn&lt;sup&gt;Au&lt;/sup&gt;, a computationally guided protein-gold hybrid nanostructure designed to combine selective recognition of aggregated Aβ with structural disruption within a defined molecular framework (Figure 1).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Aβ-binding peptide sequences were computationally screened and displayed on a human ferritin nanocage to establish multivalent Aβ recognition, while the nanocage-associated gold component provided an additional structural intervention. This design links target recognition with aggregate disruption rather than treating them as separate functions. Together, these findings illustrate how molecularly guided design may enable therapeutic agents to recognise disease-relevant Aβ assemblies and directly intervene in their pathological state.&lt;/p&gt;&lt;p&gt;Structural, mutational and computational analyses revealed how the nanostructure engages Aβ through coordinated molecular interactions, with the recognition motif and gold-associated interface contributing to sustained binding and fibril destabilisation.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Molecular dynamics simulations suggested that multivalent recognition enables sustained engagement with the fibril interface, followed by interfacial interactions that perturb β-sheet organisation and favour progressive dissociation of peripheral Aβ molecules. Together, these mechanistic observations connect the molecular architecture of &lt;sub&gt;Aβ3&lt;/sub&gt;FTn&lt;sup&gt;Au&lt;/sup&gt; with selective Aβ recognition and fibril destabilisation, providing a structural basis for its anti-amyloid activity. More broadly, these f","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104733","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":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70867","DOIUrl":"https://doi.org/10.1002/ctm2.70867","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70867","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149145680","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":"Visualizing α-synuclein pathology in live brain: A new platform for Parkinson's disease research","authors":"Minhui Yu,&nbsp;Peng Cao","doi":"10.1002/ctm2.70850","DOIUrl":"10.1002/ctm2.70850","url":null,"abstract":"&lt;p&gt;Parkinson's disease (PD) is a neurodegenerative disorder with rapidly rising prevalence and poses a significant global health concern in the coming decades.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Motor deficits (e.g., resting tremor) and non-motor features (e.g., gut motility dysfunction) together constitute its clinical picture.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; At the core of its pathogenesis lies α‑synuclein (α‑Syn),&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; a presynaptic protein encoded by the &lt;i&gt;Snca&lt;/i&gt; gene.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; In its native conformation, α-Syn remains largely unstructured, accumulates heavily at presynaptic boutons, and there governs the trafficking and fusion of synaptic vesicles.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Upon misfolding and aggregation, however, α-Syn forms Lewy bodies and Lewy neurites that progressively spread and inflict neuronal damage, and acts as a critical driver of disease progression.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; Consequently, α-Syn is considered a central target for both mechanistic studies and therapeutic development in PD. Despite this recognition, the field has long lacked technological tools capable of precisely and dynamically tracking α-Syn aggregates in the live brain, severely constraining both mechanistic studies and the development of therapeutic interventions for PD. To address this unmet need, we introduce genetically encoded fluorescent reporters for labelling α-Syn inclusions in neurons, including both &lt;i&gt;α-Syn-6H-EGFP&lt;/i&gt; and &lt;i&gt;α-Syn-6H-tdT&lt;/i&gt;, that enable direct visualization of α-Syn aggregates and their spatiotemporal propagation in the live brain, thereby offering a powerful platform for studying PD pathogenesis and advancing therapeutic development.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;To enable direct visualization of α-Syn aggregation in the live brain, we designed a series of fusion proteins by fusing mouse α-Syn to either EGFP or tdTomato (tdT) via peptide linkers. In cultured hippocampal neurons, we systematically screened seven linker variants and demonstrated that the 6-histidine (6H)-linked reporters exhibited the highest specificity and efficiency among all tested variants in labelling α-Syn inclusions induced by preformed fibrils (PFFs). Based on this result, we identified the 6H linker as the optimal design and used it to construct two reporter genes: &lt;i&gt;α-Syn-6H-EGFP&lt;/i&gt; and &lt;i&gt;α-Syn-6H-tdT&lt;/i&gt;. Notably, both reporters exhibit a notable aggregation-dependent fluorescence enhancement: when α-Syn exists as monomers, the fluorescence signal remains weak; however, upon integration into aggregates, the fluorescence intensity increases approximately five-fold. Moreover, the reporters achieve a co-localization rate of 93%–97% with phosphorylated α-Syn (p-α-Syn) inclusions, the gold-standard marker of authentic Lewy pathology,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; placing their detection accuracy at the forefront of current technologies.&lt;/p&gt;&lt;p&gt;The reporter system also demonstrates excellent biocompatibility. Through detergent extra","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104796","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":"USP25 stabilises GLI1 through K48-linked deubiquitination within a reciprocal regulatory circuit in osteoarthritis models","authors":"Qian Zhang,&nbsp;Yinyan Ye,&nbsp;Yijie Huang,&nbsp;Jun Li,&nbsp;Dongfeng Huang","doi":"10.1002/ctm2.70851","DOIUrl":"10.1002/ctm2.70851","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Osteoarthritis (OA) is characterised by progressive articular cartilage degeneration, yet effective disease-modifying targets remain limited. The post-translational mechanisms sustaining Hedgehog/&lt;i&gt;GLI1&lt;/i&gt; signalling during OA progression remain incompletely understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Bioinformatic analyses of GEO datasets were performed to evaluate &lt;i&gt;GLI1&lt;/i&gt; expression across OA-related tissue compartments. Independent cartilage datasets, paired human cartilage specimens, and primary human chondrocytes exposed to graded IL-1β stimulation provided tissue- and cell-relevant evidence. An unbiased deubiquitinase library screen combined with &lt;i&gt;GLI1&lt;/i&gt;-responsive luciferase assays was used to identify &lt;i&gt;GLI1&lt;/i&gt;-regulating deubiquitinases. The molecular function of USP25, its reciprocal regulation with &lt;i&gt;GLI1&lt;/i&gt;, and the preclinical chondroprotective activity and target dependence of AZ1 were investigated in vitro and in vivo.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;&lt;i&gt;GLI1&lt;/i&gt; dysregulation in OA cartilage and primary human chondrocytes supported subsequent screening, which prioritised USP25 for mechanistic study. In paired cartilage from 24 OA patients, USP25 protein abundance was higher in grossly degenerated than in relatively preserved regions and showed a modest positive correlation with &lt;i&gt;GLI1&lt;/i&gt;. USP25 directly interacted with &lt;i&gt;GLI1&lt;/i&gt;, removed K48-linked polyubiquitin chains, and limited its proteasomal degradation. Reciprocal gain- and loss-of-function and rescue experiments indicated that &lt;i&gt;GLI1&lt;/i&gt; substantially, but not exclusively, mediated USP25-associated inflammatory and cartilage-catabolic phenotypes. &lt;i&gt;GLI1&lt;/i&gt;, in turn, bound the &lt;i&gt;USP25&lt;/i&gt; promoter and enhanced &lt;i&gt;USP25&lt;/i&gt; transcription, establishing a reciprocal regulatory circuit. AZ1 showed preclinical chondroprotective activity in primary human chondrocytes and DMM mice. Residual AZ1 activity after USP25 silencing indicated partial USP25 dependence.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings define a &lt;i&gt;GLI1&lt;/i&gt;-centred mechanistic branch of USP25 biology in OA-relevant models and provide tissue-level support for coordinated USP25-&lt;i&gt;GLI1&lt;/i&gt; expression in human OA cartilage. The reciprocal USP25-&lt;i&gt;GLI1&lt;/i&gt; circuit contributes to cartilage-catabolic phenotypes, while AZ1 provides preclinical proof-of-concept as a pharmacological probe. Further studies are warranted to define target selectivity, long-term safety, and clinical relevance.&lt;/p&gt;\u0000 &lt;/secti","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069278","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":"Lactate metabolism and protein lactylation in programmed cell death: From novel mechanism to therapeutic strategies in human diseases","authors":"Yue Chen,&nbsp;Xiwen Wang,&nbsp;Xiuping Wang,&nbsp;Na Lin,&nbsp;Wenjie Wang,&nbsp;Ruiqi Fu,&nbsp;Yutong Wu,&nbsp;Yi Liu,&nbsp;Hengwei Liu","doi":"10.1002/ctm2.70795","DOIUrl":"https://doi.org/10.1002/ctm2.70795","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Protein lactylation is a recently identified post-translational modification that reflects cellular metabolic status. It plays an important role in regulating gene expression and maintaining essential cellular functions. Dysregulation of lactylation has been implicated in the onset and progression of various human diseases. Programmed cell death (PCD) is a fundamental biological mechanism that determines cellular fate in response to internal and external stress. Although lactylation and PCD were initially regarded as distinct biological processes, recent studies have demonstrated that lactylation directly influences key transcriptional and signaling pathways involved in multiple PCD modalities, thereby reshaping cell-death regulatory networks under pathological conditions. Nevertheless, the role of lactylation in regulating different forms of PCD across human diseases has not been fully clarified. In this review, we summarize emerging advances that reveal how histone and non-histone lactylation modulate major PCD pathways and delineate the molecular mechanisms underlying lactylation-mediated control of cell death programs. Moreover, we discuss the potential of lactylation-related regulators to serve as promising biomarkers for disease prediction and as attractive targets for therapeutic intervention. Existing studies highlight that lactylation reshapes PCD regulatory circuits under pathological conditions. Lactylation‑associated molecules exhibit great potential as candidate biomarkers for disease prediction and actionable targets for therapeutic intervention. Overall, this review deepens our understanding of how protein lactylation influences programmed cell death and offers new insights into exploiting lactylation-dependent mechanisms for targeted therapeutic development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Protein lactylation emerges as a key metabolic–epigenetic regulator linking lactate metabolism to programmed cell death.</li>\u0000 \u0000 <li>Histone and non-histone lactylation orchestrate apoptosis, pyroptosis, ferroptosis and autophagy across diverse diseases.</li>\u0000 \u0000 <li>Targeting lactylation-related pathways provides promising opportunities for disease biomarkers and therapeutic intervention.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70795","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048472","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}