Clinical and Translational Medicine最新文献

{"title":"YOD1 regulates oxidative damage of dopamine neurons in Parkinson's disease by deubiquitinating PKM2","authors":"Xia Zhao, Jinfeng Sun, Fan Chen, Hao Tang, Yuqing Zeng, Luyao Li, Qin Yu, Linjie Chen, Muzaffar Hammad, Xiaoxia Xu, Ziyao Meng, Wei Wang, Guang Liang","doi":"10.1002/ctm2.70420","DOIUrl":"https://doi.org/10.1002/ctm2.70420","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Parkinson's disease (PD) is a common neurodegenerative movement disorder, mainly characterized by the degeneration and loss of dopaminergic neurons in the substantia nigra. Oxidative stress is considered to be a key contributor to dopaminergic neuronal degeneration, triggering a series of downstream events such as mitochondrial dysfunction, neuroinflammation and misfolded protein aggregation, which ultimately exacerbate the development of PD. Deubiquitinating enzymes (DUBs) regulate oxidative stress, but their roles in PD remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>GEO database analysis and western blotting were used to analyze the expression of YOD1in PD patients and PD mouse models. Genetic knockout (KO) of YOD1 was performed to assess its effects in PD pathogenesis. The substance of YOD1 was measured via co-immunoprecipitation (Co-IP) coupled with LC-MS/MS analysis. Then the effect of YOD1-mediated motor deficits and oxidative damage were investigated using open field test, swimming test, pole test, immunofluorescence (IF) and cellular analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>YOD1 was highly expressed in PD patients and 6-OHDA-induced PD model mice and mediated reactive oxygen species (ROS) production. YOD1 KO ameliorated motor impairments and oxidative stress in PD model mice. YOD1 directly bound PKM2 and reduces its ubiquitination level by removing the K63-linked ubiquitin chain of PKM2, thereby increasing the tetramer level and reducing the dimer level of PKM2. It then inhibited dimerized PKM2 entry into the nucleus and regulated Nrf2-mediated antioxidant responses, but YOD1 does not change the stability of PKM2 protein.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study identifies YOD1 as a oxidative-sensitive regulator of PD progression, operating via the YOD1-PKM2-Nrf2 axis. Targeting YOD1 may offer a novel therapeutic strategy for PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>YOD1 is highly elevated in different PD model mice and patients with PD.</li>\u0000 \u0000 <li>YOD1 is a key regulator in oxidative stress and PD pathology.</li>\u0000 \u0000 <li>YOD1-deficient exhibit a protective effect on neuronal oxidative injury.</li>\u0000 \u0000 <li>YOD1 targets PKM2-Nrf2 axis in response to oxid","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70420","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657702","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":"Addressing osteoblast senescence: Molecular pathways and the frontier of anti-ageing treatments","authors":"Zhengdong Zhang, Pan Liu, Yu Song, Liang Ma, Yan Xu, Jie Lei, Bide Tong, Dingchao Zhu, Huaizhen Liang, Hongchuan Wang, Xingyu Zhou, Zixuan Ou, Junyu Wei, Hanpeng Xu, Di Wu, Shuchang Peng, Yifan Du, Zhi Du, Bingjin Wang, Zhiwei Liao, Wencan Ke, Kangcheng Zhao, Xiqin Xia, Lei Tan, Xiaobo Feng, Gang Liu, Shuai Li, Kun Wang, Cao Yang","doi":"10.1002/ctm2.70417","DOIUrl":"https://doi.org/10.1002/ctm2.70417","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Osteoblast senescence is a central driverof age-related osteoporosis. Accumulating evidence shows that counteractingthis senescence can substantially mitigate bone loss. In this review, we summarize the hallmarks of osteoblast senescence, the signaling pathways involved, and therapeutic strategies that target osteoblast senescence tocombat age-related osteoporosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Chronic diseases associated with ageingpose a significant threat to human health. Studies have shown that osteoporosisis closely linked to the ageing process of the body and the senescence ofosteoblasts within the bone microenvironment. Counteracting the senescence ofosteoblasts and maintaining the balance of differentiation, proliferation andfunction between osteoclasts and osteoblasts has been a key focus in the research of age-related osteoporosis and bone loss. The biological behaviour andfunctionality of the osteoblast lineage related to senescence are modulated bya variety of targets, including signalling pathways, proteins and genes associated with ageing. This review aims to discuss the senescence-related characteristics of the osteoblast lineage, dissect the interplay and mechanisms between it and ageing-associated signalling pathways, proteinsand genes, as well as current strategies for the prevention and treatment ofosteoblast senescence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review systematically examines the regulatory interactions among markers, therapeutic targets, and signalingpathways associated with osteoblast senescence, alongside current potential strategies for targeting this process. It provides more comprehensive information for future research into the complex mechanisms underlying age-related osteoporosis driven by osteoblast senescence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Osteoblast senescence is a key driver of age-related osteoporosis, disrupting bone formation and homeostasis.</li>\u0000 \u0000 <li>Aging impacts osteoblasts through multiple pathways, including telomere shortening, genomic instability, SASP secretion, and others.</li>\u0000 \u0000 <li>Bone loss related to osteoblast senescence involves the activation and crosstalk of multiple signaling pathways.</li>\u0000 \u0000 <li>The options for combating and treating osteoblast senescence toachieve anti-osteoporosis are numerous, bu","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657700","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":"PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease","authors":"Swagat Pradhan,&nbsp;Takayuki Mito,&nbsp;Nahid A Khan,&nbsp;Sofiia Olander,&nbsp;Aleksandra Zhaivoron,&nbsp;Thomas G McWilliams,&nbsp;Anu Suomalainen","doi":"10.1002/ctm2.70404","DOIUrl":"https://doi.org/10.1002/ctm2.70404","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual—extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles—respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used a mouse model for mitochondrial myopathy (“deletor”), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, <i>Pdk4</i> transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657701","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":"Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage","authors":"Shuchen Huangfu,&nbsp;Chaoting Lan,&nbsp;Sitao Li,&nbsp;Huijuan Wang,&nbsp;Chun Yan,&nbsp;Yuling Yang,&nbsp;Bowen Tian,&nbsp;Yide Mu,&nbsp;Peizhi Zhao,&nbsp;Yan Tian,&nbsp;Yijia Wang,&nbsp;Wei Zhong,&nbsp;Limei Zhong,&nbsp;Yongyan Shi,&nbsp;Yufeng Liu","doi":"10.1002/ctm2.70419","DOIUrl":"https://doi.org/10.1002/ctm2.70419","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;Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.&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;Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using &lt;i&gt;ACOD1&lt;/i&gt;&lt;sup&gt;−/-&lt;/sup&gt; and ACOD1&lt;sup&gt;fl/fl&lt;/sup&gt;LysM&lt;sup&gt;cre&lt;/sup&gt; NEC mouse models.&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;We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.&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;Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.&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;\u0000 &lt;p&gt;Itaconate alleviates NEC by reprogramming M1 macrophage metabolism&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;&lt;i&gt;ACOD1&lt;/i&gt; deficiency exacerbates NEC severity&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;4OI maintains intestinal barrier integrity.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647268","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":"Unlocking the therapeutic potential of ATR inhibitors: Advances, challenges, and opportunities in cancer therapy","authors":"Tejaswini P Reddy,&nbsp;Timothy A. Yap","doi":"10.1002/ctm2.70397","DOIUrl":"https://doi.org/10.1002/ctm2.70397","url":null,"abstract":"&lt;p&gt;The DNA damage response (DDR) and replication stress (RS) response networks consist of a highly integrated group of proteins crucial for maintaining genomic integrity and cellular survival. These networks manage DNA replication, repair, cell cycle transitions and apoptosis.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Primary regulators of the DDR are phosphoinositide 3-kinase related protein kinases (PIKKs), notably ataxia telangiectasia mutated (ATM) and Rad-3 related (ATR). ATR can be activated in response to extensive single-stranded DNA breaks (ssDNA) at stalled replication forks and other forms of replication stress, triggering downstream reactions, such as the phosphorylation of serine-threonine kinase Chk1. The ATR-Chk1 signalling cascade plays a key role in various biological processes, including mitotic cell cycle checkpoint regulation, replication fork stabilization and remodelling, suppression of replication origin firing, regulation of nucleotide pools, meiotic cell cycle progression, and management of cellular mechanical stress and inflammatory processes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Deficiencies in the DDR and RS response lead to genomic instability, promoting cancer initiation and progression through mutation accumulation. However, these deficiencies also create therapeutic vulnerabilities in cancer cells, allowing for the development of rational molecularly targeted agents against the DDR, such as ATR inhibitors (Figure 1).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; This approach has been clinically validated with poly(ADP-ribose) polymerase (PARP) inhibitors, which have obtained regulatory approval in different tumour types with &lt;i&gt;BRCA1&lt;/i&gt; or &lt;i&gt;BRCA2&lt;/i&gt; loss-of-function (LOF) mutations.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The rationale for targeting ATR as a therapeutic strategy for various cancer types with DDR defects lies in the fact that ATR inhibition disrupts mechanisms described above that maintain genomic integrity. This disruption leads to genomic instability, causing premature entry into mitosis regardless of RS or DNA damage. This triggers mitotic catastrophe and cellular apoptosis, processes that may be synthetically lethal in cancer cells with DDR defects, such as ATM LOF mutations.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The development of ATR inhibitors originated from studies showing that inhibitory mutations of the ATR kinase domain were primarily hypomorphic or partially inhibitory. ATR also plays other biological roles independent of its kinase activity, such as suppressing mechanical stress and inflammation, which we can therapeutically exploit when combining ATR inhibitors with immunotherapies. Therefore, incomplete or hypomorphic ATR inhibition may represent a promising anti-cancer therapeutic strategy.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;ATR inhibitors that have been assessed in clinical trials include the intravenously administered drug berzosertib, and orally administered drugs camosertib, ceralasertib, elimusertib, tuvusertib, ART0380, ATRN-119, ATG-018 and I","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647678","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":"Cancer therapy resistance from a spatial-omics perspective","authors":"Yinghao Zhang,&nbsp;Cheng Yang,&nbsp;Xi Chen,&nbsp;Liang Wu,&nbsp;Zhiyuan Yuan,&nbsp;Fan Zhang,&nbsp;Bin-Zhi Qian","doi":"10.1002/ctm2.70396","DOIUrl":"https://doi.org/10.1002/ctm2.70396","url":null,"abstract":"<p>Cancer therapy resistance (CTR) remains a significant challenge in oncology. Traditional methods like imaging, liquid biopsies and conventional omics analyses provide valuable insights, but lack the spatial resolution to fully characterise heterogeneity of tumour and the tumour microenvironment (TME). Recent advancements in spatial omics technologies offer unprecedented insights into the spatial organisation of tumours and TME. In this review, we summarise current methodologies for CTR research and highlight how spatial omics technologies and computational methods are revolutionising our understanding of CTR mechanisms. We also summarise recent studies leveraging spatial omics to uncover novel insights into CTR across various cancer types and therapies and discuss future opportunities.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70396","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647517","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":"Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer","authors":"Pei Lin,&nbsp;Yunfan Lin,&nbsp;Xu Chen,&nbsp;Xinyuan Zhao,&nbsp;Li Cui","doi":"10.1002/ctm2.70403","DOIUrl":"https://doi.org/10.1002/ctm2.70403","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional repression, lysosomal degradation, and post-translational modifications that disrupt MHC stability, trafficking, and surface expression. We highlight how these mechanisms impair antigen presentation and contribute to tumour immune evasion. In addition, we explore emerging therapeutic strategies focused on reactivating MHC expression to enhance tumour immunogenicity and improve the efficacy of immunotherapy. Finally, we discuss the translational potential of these approaches and the remaining challenges, including tumour heterogeneity, immunotoxicity and dynamic regulation within the tumour microenvironment, that must be addressed to optimize MHC-targeted interventions in cancer immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Tumour cells evade immune surveillance by downregulating MHC expression through transcriptional repression, lysosomal degradation and post-translational modifications.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Pharmacological agents interventing epigenetic and metabolic can upregulate MHC expression and improve T cell activation.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Combination strategies potentiate immunotherapy efficacy by reinvigorating tumour immunogenicity.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647267","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":"Interleukin-11 promotes lung adenocarcinoma tumourigenesis and immune evasion","authors":"Cristina Cirauqui,&nbsp;Laura Ojeda,&nbsp;Itziar Otano,&nbsp;Irene Pazos,&nbsp;Alba Santos,&nbsp;Eva M. Garrido-Martín,&nbsp;Patricia Yagüe,&nbsp;Javier Ramos-Paradas,&nbsp;Sonia Molina-Pinelo,&nbsp;Giovanna Roncador,&nbsp;José Luis Solórzano,&nbsp;M. Teresa Muñoz,&nbsp;Patricia Cozar,&nbsp;Patricia Plaza,&nbsp;Rocío Suárez,&nbsp;Marta Jiménez,&nbsp;Roberto Moreno,&nbsp;Arantxa Rosado,&nbsp;Pablo Gámez,&nbsp;Ricardo García-Luján,&nbsp;Jon Zugazagoitia,&nbsp;E. Alejandro Sweet-Cordero,&nbsp;Mariano Barbacid,&nbsp;Amancio Carnero,&nbsp;Irene Ferrer,&nbsp;Luis Paz-Ares","doi":"10.1002/ctm2.70374","DOIUrl":"https://doi.org/10.1002/ctm2.70374","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rationale</h3>\u0000 \u0000 <p>Interleukin-11 (IL-11) has emerged as a significant player in tumourigenesis, with implications across various cancer types. However, its specific role in driving tumour progression in lung adenocarcinoma (LUAD) remains elusive. IL-11's multifaceted impact on both tumour cells and the tumour microenvironment underscores its potential as a therapeutic target in LUAD. This study aims to unravel the involvement of IL-11 in LUAD progression and its influence on the tumour microenvironment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we used transcriptomic and digital spatial profiling analyses together with clinic data from two retrospective LUAD patient cohorts. LUAD cell lines genetically engineered to overexpress or to silence IL-11 or its receptor (IL-11RA) were used for in vitro functional analysis and for in vivo experiments. Additionally, we used three different in vivo models: patient-derived xenografts (PDXs), tobacco-exposed mice and genetically engineered mouse models. A neutralising monoclonal antibody against IL-11RA was produced and tested.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed a pivotal role for IL-11 in driving tumourigenesis across various mouse models, highlighting its capacity to modulate tumour immunity towards an immunosuppressive microenvironment. Moreover, we observed a correlation between IL-11 expression and poorer patient outcomes in LUAD. Notably, therapeutic targeting of IL-11RA with a neutralising antibody demonstrated significant anti-tumour efficacy in a PDX model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The IL-11/IL-11RA axis emerges as a critical driver of LUAD tumourigenesis, exerting its effects through enhanced tumour cell proliferation and remodelling of the tumour microenvironment. Our study highlights the therapeutic potential of disrupting this axis, suggesting that patients exhibiting elevated IL-11 levels may benefit from therapies targeting the IL-11/IL-11RA pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647516","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":"Asymmetric bilayer dressings with spatiotemporal sequence loaded with IL-24 and GCDs for the treatment of diabetic wounds","authors":"Sijia Li,&nbsp;Jinjin Lu,&nbsp;Nianqiang Jin,&nbsp;Yuan Su,&nbsp;Songning Han,&nbsp;Jiankang He,&nbsp;Wenqiang Xie","doi":"10.1002/ctm2.70402","DOIUrl":"https://doi.org/10.1002/ctm2.70402","url":null,"abstract":"<p>Dear Editor</p><p>Diabetic wounds pose a significant global health challenge, affecting hundreds of millions of diabetes patients and imposing substantial financial burdens on healthcare systems.<span>¹</span> Despite conventional treatments, the underlying mechanisms remain poorly understood, resulting in unsatisfactory clinical outcomes. Diabetic wounds exhibit severely impaired fibroblast-to-myofibroblast transition (FMT), a process essential for wound contraction and matrix remodelling. Hyperglycaemia, advanced glycation end products, and chronic inflammation disrupt key signalling pathways regulating FMT, resulting in deficient myofibroblast differentiation and compromised wound healing.<span>²</span> Recent biomaterial advances in diabetic wound care include hydrogel dressings incorporating growth factors, cytokines, and antimicrobial agents. However, current approaches typically target single mechanisms and fail to simultaneously address impaired cellular function, bacterial infection, and chronic inflammation—the complex interplay characterising diabetic wounds.<span>³</span> Interleukin-24 (IL-24) exhibits exceptional promise in stimulating cellular proliferation, differentiation, and extracellular matrix production.<span>⁴</span> We postulate that IL-24 may facilitate the impaired FMT, thereby enhancing diabetic wound repair. Nevertheless, clinical application encounters significant obstacles, including potential bacterial attraction and challenges in maintaining stable, sustained local delivery at wound sites.<span>⁵</span> To address IL-24′s bacterial chemotaxis, we incorporated ginseng-derived carbon quantum dots (GCDs) possessing wide-ranging antimicrobial effects and superior biocompatibility.<span>⁶</span> In this study, we discovered significant IL-24 upregulation during diabetic wound healing. Using IL-24 knockout mice, we demonstrated that IL-24 promotes healing by inducing FMT through in vivo and in vitro experiments. Building on these findings, we developed a novel asymmetric dual-layer hydrogel dressing. The tissue side layer delivers IL-24 to enhance FMT, while the outside layer, containing GCDs, provides antibacterial effects through reactive oxygen species (ROS) release. Animal models confirmed this dressing's dual efficacy in promoting wound healing and preventing infection. Our findings establish IL-24 as a promising therapeutic target and demonstrate that this dual-layer hydrogel represents an innovative strategy for diabetic wound management.</p><p>Analysis of gene expression signatures from GEO databases revealed significant IL-24 upregulation in diabetic wounds, demonstrating expression patterns parallel to established wound healing genes (Figure 1A–C). We confirmed these bioinformatic findings through immunohistochemical (IHC) analysis of STZ-induced diabetic C57 mice, which validated elevated IL-24 expression in diabetic wound tissues (Figure 1D–","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70402","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647340","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":"Towards a quantum therapy in cancer","authors":"Frankie James Rawson","doi":"10.1002/ctm2.70411","DOIUrl":"https://doi.org/10.1002/ctm2.70411","url":null,"abstract":"&lt;p&gt;Bioelectricity&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and quantum&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; effects are increasingly recognised as fundamental mechanisms in biology underpinning various disease processes, offering new paradigms for therapeutic interventions. The article “Wireless electrical–molecular quantum signalling for cancer cell apoptosis”.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; introduces an innovative and potentially transformative approach to cancer treatment through the use of quantum biological tunnelling&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; facilitated by wireless nano-electrochemical tools. This groundbreaking research highlights the intersection of nanotechnology, quantum biology and oncology, providing a new paradigm for cancer cell apoptosis.&lt;/p&gt;&lt;p&gt;The study leverages gold bipolar nanoelectrodes functionalised with redox-active cytochrome c and zinc porphyrin, termed bio-nanoantennae, to regulate electron transport via a remote electrical input. This novel approach enabled selective triggering of apoptosis in patient-derived cancer cells, specifically glioblastoma (GBM) cells, demonstrating a significant advancement in targeted cancer therapy (Figure 1).&lt;/p&gt;&lt;p&gt;The significance of this research lies in its ability to harness quantum mechanical effects for biological applications, specifically in modulating cellular functions. The development of bio-nanoantennae capable of inducing apoptosis through wireless electrochemistry represents a novel tool in the arsenal against cancer. This method circumvents traditional limitations of drug delivery and specificity, offering a highly targeted approach that minimises collateral damage to surrounding healthy tissues.&lt;/p&gt;&lt;p&gt;The research elucidated the underlying mechanism of action where the application of an alternating current (a.c.) electric field induces quantum biological tunnelling for electron transfer. This electron transfer is crucial for the redox state modulation of cytochrome c, switching from its reduced (Fe&lt;sup&gt;2+&lt;/sup&gt;) to oxidised (Fe&lt;sup&gt;3+&lt;/sup&gt;) state, which is known to trigger apoptotic pathways.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The study's use of transcriptomics to analyse the gene expression changes further supports the specificity and effectiveness of the bio-nanoantennae in inducing apoptosis (Figure 2).&lt;/p&gt;&lt;p&gt;An important finding of the study is the necessity of efficient endosomal escape for nanoparticles to exert therapeutic effects, aligning with current research from the Rawson group. They demonstrated that high-frequency alternating current (HF-AC) regulates endosomal escape, enhancing the bioavailability of therapeutic nanoparticles in the cytoplasm. Jain et al. support this,&lt;span&gt;&lt;sup&gt;2, 6&lt;/sup&gt;&lt;/span&gt; showing HF-AC facilitates gold nanoparticle (GNP) escape from endosomes in GBM cells, increasing their cytoplasmic concentration and efficacy.&lt;/p&gt;&lt;p&gt;The study presents a key technological advancement in designing gold bipolar nanoelectrodes, functioning as bio-nanoantennae for wireless electrochemical int","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70411","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635414","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}