Clinical and Translational Medicine最新文献

{"title":"Correction to “Inflammasome activation and metabolic remodeling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1”","authors":"","doi":"10.1002/ctm2.70379","DOIUrl":"https://doi.org/10.1002/ctm2.70379","url":null,"abstract":"<p>Gu X, Meng H, Peng C, et al. Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1. <i>Clin Transl Med</i>. 2023;13(6):1308.</p><p>In this article, the authors have just realized the wrong usages of immunoblotting bands for β-gal and p16 presented in Figure S1D and immunoblotting band for K48-polyubiquitin (Ub) presented in Figure S12K. The corrected Figures S1D and S12K are as follows. The quantitative analysis in Figure S1F has been conducted using this accurate immunoblotting result of Figures S1D.</p><p>The authors sincerely apologize for these errors. This correction does not affect the study's conclusions.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695907","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":"Early molecular changes predict cancer cachexia in LKB1-deleted mouse models of NSCLC","authors":"Gloriana Ndembe,&nbsp;Andrea David Re Cecconi,&nbsp;Federica Palo,&nbsp;Dorina Belotti,&nbsp;Laura Sala,&nbsp;Selena Foroni,&nbsp;Eugenio Scanziani,&nbsp;Rosanna Piccirillo,&nbsp;Massimo Broggini,&nbsp;Mirko Marabese","doi":"10.1002/ctm2.70360","DOIUrl":"https://doi.org/10.1002/ctm2.70360","url":null,"abstract":"&lt;p&gt;Dear Editor&lt;/p&gt;&lt;p&gt;This preclinical study highlights the potential for early cachexia assessment in LKB1-deficient non–small-cell lung cancer (NSCLC) by molecular analysis of multiple tissues. In addition, it opens new avenues for investigating the role of IL-12 as a protective factor against NSCLC-related cachexia.&lt;/p&gt;&lt;p&gt;To investigate the role of LKB1 in cancer-related cachexia, we used mouse cell lines derived from transgenic lung tumour nodules.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; These cell lines, deleted in LKB1 but harbouring different Kirsten rat sarcoma virus (KRAS) mutations and the site of injection, were injected into immunocompetent mice. Regardless of the type of KRAS mutation, LKB1 deletion was associated with body weight loss (Figure S1).&lt;/p&gt;&lt;p&gt;To assess the possible role of sex,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; we injected KRAS&lt;sup&gt;G12D&lt;/sup&gt; (K) and KRAS&lt;sup&gt;G12D&lt;/sup&gt;/LKB1&lt;sup&gt;−/−&lt;/sup&gt; (KL) NSCLC cells in male and female mice. K tumours grew faster than KL tumours in both sexes, with male mice facing faster overall tumour growth (Figures 1A and S2). Mice bearing KL tumour experienced rapid body weight loss, which was more pronounced in females. On day 26 post-inoculation, KL mice had significantly lower body weights than K or control mice, whereas K mice had body weights similar to those of the control mice (Figure 1B,C).&lt;/p&gt;&lt;p&gt;At sacrifice, KL mice showed statistically significant reductions in the gastrocnemius, tibialis anterior (TA) and soleus muscle weights. The extensor digitorum longus (EDL) muscle weight was significantly reduced only in females. Male K mice exhibited a significant reduction in gastrocnemius and TA muscle weights, while female K mice showed decreased soleus muscle weight (Figure 1D–G). Male KL mice also showed a severe reduction in visceral adipose tissue, which was completely absent in females. K tumours were associated with hepatosplenomegaly, whereas KL tumours were associated with liver mass reduction, especially in females (Figure 1H–J).&lt;/p&gt;&lt;p&gt;Histological analysis revealed hepatocellular atrophy, apoptosis, Kupffer cell hyperplasia and neutrophil infiltration in KL tumour-bearing mice (Figure S3). Food consumption remained unchanged before weight loss, but KL females showed reduced consumption at later stages. K mice showed no differences in food intake (Figure S4). Immunocompromised KL-bearing female mice also experienced weight loss, suggesting that the immune system is not the primary driver. In these animals also, K tumours grew faster than KL (Figure S5).&lt;/p&gt;&lt;p&gt;IL-6, a key mediator of cachexia,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; was upregulated in KL cells compared to K cells in vitro (Figure 1K,L). In vivo, KL tumours showed higher IL-6 expression than K tumours, especially in males (Figure 1M). Liver IL-6 expression was elevated in both K and KL mice, with KL showing the highest levels (Figure 1N). IL-6 expression in the spleen differed by sex: in females, only KL tumours bearing mice showed IL-6 upregulation, wh","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687912","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":"Spatially resolved proteomics surveys the chemo-refractory proteins related to high-grade serous ovarian cancer","authors":"Linyuan Fan,&nbsp;Yi Liu,&nbsp;Haichao Zhou,&nbsp;Yang Feng,&nbsp;Guangyi Jiang,&nbsp;Guixue Hou,&nbsp;Zhihan Cao,&nbsp;Zhiguo Zheng,&nbsp;Lu Sun,&nbsp;Hao Chen,&nbsp;Yuefei Zhang,&nbsp;Weiran Chen,&nbsp;Yun Xi,&nbsp;Benliang Cheng,&nbsp;Qinghai Yang,&nbsp;Yan Ren,&nbsp;Jianqing Zhu,&nbsp;Siqi Liu","doi":"10.1002/ctm2.70422","DOIUrl":"https://doi.org/10.1002/ctm2.70422","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>High-grade serous ovarian carcinoma (HGSC) is a lethal malignancy characterized by high incidence, mortality, and chemoresistance. However, its molecular drivers are unknown. In this study, spatially resolved proteomics was applied to 1144 formalin-fixed paraffin-embedded tissue spots obtained by laser capture microdissection from 10 patients with HGSC and divergent carboplatin-paclitaxel (CP) responses. Specific sampling revealed stroma-driven tumour heterogeneity, identifying 642 tumour-specific and 180 stroma-specific proteins, with 505 CP-responsive therapeutic targets. Most of these protein signatures represented previously unreported associations with chemoresistance in HGSCs. Two clinically significant spatial proteomic maps were generated by introducing tumour (TS) and chemical (CS) scores. TS analysis revealed conserved tissue architecture across CP response groups, whereas CS mapping revealed pretreatment metabolic reprogramming (rather than proliferation) as the defining feature of chemo-resistant tumours, challenging current resistance paradigms. Immunohistochemical validation of HGSC tissue microarrays confirmed the spatial proteomic localization of TFRC and PDLIM3, which are linked to tumour progression, while establishing their novel role as chemotherapy resistance biomarkers through this study, with broader predictive potential observed across additional targets in the discovery cohort. This study developed a spatially resolved proteomic framework to enhance the diagnostic and therapeutic strategies for HGSC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>HGSC intra-tumour heterogeneity is predominantly driven by stroma, as revealed by spatial proteomic compartmentalization (tumour/stroma).</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Spatial proteomics expands the therapeutic target database, enabling prediction of platinum-based chemotherapy response.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Chemo-resistant patients exhibit pre-treatment metabolic activation rather than proliferative signatures.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>TFRC (iron transport) and PDLIM3 (cytoskeletal remodelling) are spatially validated as chemo-response biomarkers.</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":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70422","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681607","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":"Precision treatment in breast cancer: Leveraging genetic interactions","authors":"Cai-Jin Lin,&nbsp;Xin Hu,&nbsp;Zhi-Ming Shao,&nbsp;Yi-Zhou Jiang","doi":"10.1002/ctm2.70407","DOIUrl":"https://doi.org/10.1002/ctm2.70407","url":null,"abstract":"&lt;p&gt;The advent of next-generation sequencing technology has catalyzed significant advancements in precision treatment strategies for breast cancer by leveraging insights into individual tumour genomes.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; This genome-guided approach has notably enhanced therapeutic outcomes, particularly in patients with specific genomic alterations (Figure 1).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; For example, anti-HER2 targeted therapies exemplify a classical form of genotype-matched treatment specifically designed to target gene products in &lt;i&gt;ERBB2&lt;/i&gt;-amplified breast cancers.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; However, despite the initial success of precision treatment in breast cancer, clinical endeavours targeting individual alterations have yielded variable efficacy. One important reason is that clinical decision-making for precision treatment has overly focused on single driver alterations without considering potential interactions among multiple genomic alterations and their impact on efficacy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The concept of genetic interactions, encompassing both the co-occurrence and mutual exclusivity of genomic alterations, highlights the complexity underlying breast cancer biology and treatment response.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Specifically, co-occurring genomic alterations can synergistically impact tumour behaviour and therapeutic responses (Figure 1). Targeting only one genomic alteration may lead to the development of drug resistance, whereas simultaneous targeting of both events has the potential to effectively eradicate the tumour. For instance, the presence of &lt;i&gt;PIK3CA&lt;/i&gt; co-mutations has been associated with poorer prognosis under anti-HER2 therapy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In addition, interactions such as &lt;i&gt;HER2-HER3&lt;/i&gt; co-alteration influencing neratinib response via PI3K activation illustrate potential mechanisms of treatment resistance that can be overcome through a combination therapy of neratinib and PI3Kα inhibitors.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Despite some existing insights into mutation-treatment interactions,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; comprehensive investigations into the broader landscape of genetic interactions and their implications for treatment outcomes remain crucial.&lt;/p&gt;&lt;p&gt;These challenges necessitate a comprehensive investigation of genetic interactions, especially co-occurrences, and their association with treatment outcomes in breast cancer. Accordingly, we developed a comprehensive network of genetic interactions specific to breast cancer, identifying 50 instances of co-occurrence and 30 instances of mutual exclusivity.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; This network not only reaffirms known associations, such as the co-occurring &lt;i&gt;TP53&lt;/i&gt; mutation and &lt;i&gt;MYC&lt;/i&gt; copy number amplification, as well as mutually exclusive mutations between &lt;i&gt;PIK3CA&lt;/i&gt; and &lt;i&gt;AKT1&lt;/i&gt;, but also unveils novel genetic interactions, such as the co-occurring &lt;i&gt;TP53&lt;/i&gt; mutation and &lt;i&gt;MYB&lt;/i&gt; copy number amplification, previou","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687910","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":"Glutamate as a therapeutic strategy to promote liver regeneration","authors":"María del Mar Rigual,&nbsp;Nabil Djouder","doi":"10.1002/ctm2.70421","DOIUrl":"https://doi.org/10.1002/ctm2.70421","url":null,"abstract":"&lt;p&gt;Rigual MdM, Djouder N. Glutamate as a therapeutic strategy to promote liver regeneration. &lt;i&gt;Clin Transl Med&lt;/i&gt;. 2025;00:e70421. https://doi.org/10.1002/ctm2.70421&lt;/p&gt;&lt;p&gt;The intrinsic regenerative capacity of the liver is crucial for recovery following injury, surgical resection, or transplantation. However, in patients with chronic liver disease or extensive hepatectomy, this capacity is often compromised, limiting therapeutic outcomes. Recent findings uncover a novel, metabolically driven mechanism of liver regeneration centred on glutamate signalling. Following hepatic injury, downregulation of unconventional prefoldin RPB5 interactor 1 (URI1) in pericentral hepatocytes leads to reduced glutamine synthetase (GS) activity and elevated systemic glutamate levels. This circulating glutamate activates bone marrow-derived macrophages, which migrate to the liver, stabilise hypoxia-inducible factor 1-alpha (HIF1α), and secrete Wnt3, initiating YAP1-driven hepatocyte proliferation and effective tissue repair. Importantly, glutamate supplementation was shown to robustly promote liver regeneration and increase survival in preclinical models, including cirrhosis and 90% hepatectomy. These findings identify a clinically actionable metabolic-immune axis and suggest that oral physiological concentration of glutamate supplementation could serve as a safe, affordable adjunct therapy for patients undergoing liver resection, transplantation, or managing chronic liver failure. In addition, the potential development of URI1 inhibitors could offer an additional pharmacological approach to modulate this regenerative pathway. Together, this work represents a paradigm shift in regenerative hepatology, establishing glutamate as a key therapeutic driver of liver repair and opening the door to clinical trials aiming to validate its efficacy and safety in human patients.&lt;/p&gt;&lt;p&gt;The liver is a vital organ responsible for metabolic homeostasis and detoxification, rendering it particularly susceptible to injury from alcohol, drugs, environmental toxins, and dietary factors. Remarkably, despite continuous exposure to harmful agents, the liver possesses a unique and robust regenerative capacity. Hepatocytes, the principal functional cells of the liver and the cells that shoulder the regenerative process, are typically quiescent under normal conditions but can rapidly proliferate in response to tissue damage.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This regenerative process is crucial for recovery from acute damage and for maintaining liver mass and function.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, after chronic or repeated injury, the liver regenerative capacity declines significantly, impairing the classic regenerative program and limiting the ability of hepatocytes to proliferate. This reduction in regenerative potential is a major clinical problem, especially for patients with chronic liver diseases or liver cancer requiring surgical resection, such as tumour removal or liver transp","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666152","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":"YOD1 regulates oxidative damage of dopamine neurons in Parkinson's disease by deubiquitinating PKM2","authors":"Xia Zhao,&nbsp;Jinfeng Sun,&nbsp;Fan Chen,&nbsp;Hao Tang,&nbsp;Yuqing Zeng,&nbsp;Luyao Li,&nbsp;Qin Yu,&nbsp;Linjie Chen,&nbsp;Muzaffar Hammad,&nbsp;Xiaoxia Xu,&nbsp;Ziyao Meng,&nbsp;Wei Wang,&nbsp;Guang Liang","doi":"10.1002/ctm2.70420","DOIUrl":"https://doi.org/10.1002/ctm2.70420","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;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.&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;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.&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;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.&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 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.&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;YOD1 is highly elevated in different PD model mice and patients with PD.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;YOD1 is a key regulator in oxidative stress and PD pathology.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;YOD1-deficient exhibit a protective effect on neuronal oxidative injury.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;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,&nbsp;Pan Liu,&nbsp;Yu Song,&nbsp;Liang Ma,&nbsp;Yan Xu,&nbsp;Jie Lei,&nbsp;Bide Tong,&nbsp;Dingchao Zhu,&nbsp;Huaizhen Liang,&nbsp;Hongchuan Wang,&nbsp;Xingyu Zhou,&nbsp;Zixuan Ou,&nbsp;Junyu Wei,&nbsp;Hanpeng Xu,&nbsp;Di Wu,&nbsp;Shuchang Peng,&nbsp;Yifan Du,&nbsp;Zhi Du,&nbsp;Bingjin Wang,&nbsp;Zhiwei Liao,&nbsp;Wencan Ke,&nbsp;Kangcheng Zhao,&nbsp;Xiqin Xia,&nbsp;Lei Tan,&nbsp;Xiaobo Feng,&nbsp;Gang Liu,&nbsp;Shuai Li,&nbsp;Kun Wang,&nbsp;Cao Yang","doi":"10.1002/ctm2.70417","DOIUrl":"https://doi.org/10.1002/ctm2.70417","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;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.&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;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&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;Osteoblast senescence is a key driver of age-related osteoporosis, disrupting bone formation and homeostasis.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Aging impacts osteoblasts through multiple pathways, including telomere shortening, genomic instability, SASP secretion, and others.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Bone loss related to osteoblast senescence involves the activation and crosstalk of multiple signaling pathways.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;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}