Clinical and Translational Medicine最新文献

{"title":"Ferroptosis of T cell in inflammation and tumour immunity","authors":"Xueli Xia,&nbsp;Haisheng Wu,&nbsp;Yuxuan Chen,&nbsp;Huiyong Peng,&nbsp;Shengjun Wang","doi":"10.1002/ctm2.70253","DOIUrl":"https://doi.org/10.1002/ctm2.70253","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Ferroptosis is an innovative concept defined as a distinct programmed cell death mode regulated by iron-dependent lipid peroxidation accumulation. This process is governed by numerous energy metabolites such as fatty acids, amino acids and glucose, as well as iron homeostasis. In recent years, increasing studies have been devoted to the crucial effects of ferroptosis in immune cells during the pathogenesis of diseases such as infections, tumours and autoimmune disorders. This review summarises the latest advancements in T-cell ferroptosis, addresses the key components and mechanism of ferroptosis in T cells during inflammatory conditions and tumour progression, and highlights the potential target for treating related diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Ferroptosis-related mechanisms significantly affect the biology of CD4⁺ T-cell subsets and are further involved in inflammatory diseases.</li>\u0000 \u0000 <li>Crosstalk between CD8⁺ T cells and tumour cells induces ferroptosis in the tumour microenvironment.</li>\u0000 \u0000 <li>Glutathione peroxidase 4 loss promotes regulatory T-cell ferroptosis to enhance anti-tumour immunity.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554475","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":"Fusobacterium nucleatum promotes anastomotic leakage by activating epithelial cells through the NOD1/RIPK2/ERK signalling pathway to drive IL-1β-induced neutrophil chemotaxis and collagen degradation","authors":"Zixian Wei,&nbsp;Liqing Bao,&nbsp;Bowen Li,&nbsp;Jinhua Yang,&nbsp;Jijiao Wang,&nbsp;Fangqi Xu,&nbsp;Hubin Wenren,&nbsp;Kunyu Zhang,&nbsp;Shang Shi,&nbsp;Liying Yan,&nbsp;Xin Tao,&nbsp;Tianqi Zhang,&nbsp;Zhiyue Wang,&nbsp;Yang Liu","doi":"10.1002/ctm2.70262","DOIUrl":"https://doi.org/10.1002/ctm2.70262","url":null,"abstract":"&lt;p&gt;Dear Editor:&lt;/p&gt;&lt;p&gt;We herein suggest that &lt;i&gt;Fusobacterium nucleatum&lt;/i&gt; (&lt;i&gt;F. nucleatum&lt;/i&gt;) disrupts anastomotic healing. It promotes the movement and activation of neutrophils, which increases MMPs production. These MMPs break down collagen, weakening the anastomosis and causing leakage.&lt;/p&gt;&lt;p&gt;Anastomotic leakage (AL) is a critical and potentially fatal complication that may arise following colorectal surgery.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Despite its clinical significance, no specific risk factors or surgical techniques have been identified that can effectively improve anastomotic healing.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Recent studies indicate a possible connection between gut microbiota imbalances and the occurrence of AL.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; We previously demonstrated an increased abundance of &lt;i&gt;F. nucleatum&lt;/i&gt; in patients who developed AL.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Inflammation has been implicated in anastomotic leakage (AL), with neutrophils (NEs) being the main inflammatory cells involved in acute colitis.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Matrix metalloproteinases (MMPs) play a crucial role in tissue damage associated with AL.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; Neutrophils contribute to tissue breakdown in AL by releasing MMPs.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; This study aims to investigate the impact of &lt;i&gt;F. nucleatum&lt;/i&gt; on AL, with a particular emphasis on the role of neutrophils in this process.&lt;/p&gt;&lt;p&gt;To establish that &lt;i&gt;F. nucleatum&lt;/i&gt; colonisation induces AL, we developed a colon anastomotic healing model in germ-free rederivation mice. Mice were inoculated via enema with &lt;i&gt;F. nucleatum&lt;/i&gt;, &lt;i&gt;E. coli&lt;/i&gt;, or PBS from the day of surgery (POD0) to POD3. All mice were sacrificed on POD7, and a laparotomy was performed to assess the gross anastomotic healing (Figure 1A). &lt;i&gt;F. nucleatum&lt;/i&gt; colonised both mucosal and submucosal layers (Figure 1B and C), leading to poor anastomotic healing, as evidenced by leakage, peritoneal contamination, and visible dehiscence (Figure 1D). The anastomotic healing scores were higher (poorer healing) in the &lt;i&gt;F. nucleatum&lt;/i&gt; group, with increased inflammatory cell infiltration (Figure 1E) and weak collagen deposition (Figure 1F). Neutrophil activation and enhanced MMP9 deposition were observed (Figure 1G), with gelatin zymography showing increased MMP9 and NGAL-MMP9 (Figures 1H and J). Collagenase activity was also elevated (Figure 1I), and multiplex immunofluorescence revealed co-localisation of &lt;i&gt;F. nucleatum&lt;/i&gt;, MMP9, and neutrophil markers, linked to reduced collagen deposition (Figure 1K). All these suggest that &lt;i&gt;F. nucleatum&lt;/i&gt; contribute to neutrophil activation and collagen degradation contribute to AL.&lt;/p&gt;&lt;p&gt;To evaluate the direct influence of &lt;i&gt;F. nucleatum&lt;/i&gt; on neutrophils, we infected neutrophils with &lt;i&gt;F. nucleatum&lt;/i&gt; in vitro. This led to neutrophil activation, as evidenced by an increase in reactive oxygen species (ROS) production (Figure S1F). The MMPs activity in neutrophil culture supern","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70262","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel GSDMD inhibitor GI-Y2 exerts antipyroptotic effects to reduce atherosclerosis","authors":"Xiaoxi Fan,&nbsp;Zhenfeng Cheng,&nbsp;Ruiyin Shao,&nbsp;Keke Ye,&nbsp;Xudong Chen,&nbsp;Xueli Cai,&nbsp;Shanshan Dai,&nbsp;Zhixuan Tang,&nbsp;Si Shi,&nbsp;Wenyuan Zheng,&nbsp;Weijian Huang,&nbsp;Jibo Han,&nbsp;Bozhi Ye","doi":"10.1002/ctm2.70263","DOIUrl":"https://doi.org/10.1002/ctm2.70263","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gasdermin D (GSDMD) and the pyroptosis it mediates are importantly involved in cardiovascular diseases (CVDs). Identifying and developing new inhibitors of GSDMD could be a promising strategy for treating pyroptosis-mediated diseases, such as atherosclerosis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We aimed to develop new inhibitor of GSDMD in atherosclerosis, as well as clarify the mechanisms underlying this inhibiting effect.&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;Surface plasmon resonance and pull-down assay were used to identify the amino acid sites of GSDMD inhibited by GI-Y2. A mouse model of atherosclerosis was established by feeding a high-fat diet for 12 weeks. After treating mice with GI-Y2 (10 or 20 mg/kg, &lt;i&gt;i.g&lt;/i&gt;.), the lipid plaque area on the arterial intimal surface, lipid deposition, collagen deposition and pyroptosis levels in aortic root sections were evaluated. Additionally, further treatment of atherosclerotic mice with macrophage membrane-encapsulated GI-Y2 was conducted to enhance the targeting ability of GI-Y2 to atherosclerotic plaques.&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;In this study, we confirmed GI-Y2 as a novel inhibitor of GSDMD via structure-based virtual screening and pharmacological validation. Mechanistically, GI-Y2 directly interacts with the Arg10 residue of GSDMD and reduces the membrane binding of GSDMD-N. Functionally, we revealed that GI-Y2 inhibits the formation of atherosclerotic plaques by targeting GSDMD. Similarly, GI-Y2 reduces pyroptosis and macrophage infiltration in atherosclerosis. Furthermore, we constructed macrophage membrane-coated GI-Y2 nanoparticles to enhance the targeting of GI-Y2 to macrophages in atheromatous plaques and demonstrated its vascular protective effect in vivo.&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 work demonstrated that GI-Y2 can potentially alleviate CVDs by targeting GSDMD and provided a new compound for the study of GSDMD-mediated pyroptosis.&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;We preliminarily confirmed GI-Y2 as a novel inhibitor of GSDMD via structure-based virtual screening and pharmacological validation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;GI-Y2 directly interacts with GSDMD and reduc","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554476","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":"Chimeric antigen receptor T cell therapy based on stem cell-like memory T cells enhances anti-tumour effects in multiple myeloma","authors":"Zhaoyun Liu,&nbsp;Xintong Xu,&nbsp;Yihao Wang,&nbsp;Panpan Cao,&nbsp;Jia Song,&nbsp;Kai Ding,&nbsp;Hui Liu,&nbsp;Rong Fu","doi":"10.1002/ctm2.70264","DOIUrl":"https://doi.org/10.1002/ctm2.70264","url":null,"abstract":"&lt;p&gt;To the Editor,&lt;/p&gt;&lt;p&gt;Multiple myeloma (MM) is the second largest malignant tumour of the haematological system.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Nowadays, chimeric antigen receptor T-cell (CAR-T) therapy has become a revolutionary approach to the treatment of MM, significantly prolonging progression-free survival (PFS) and overall survival (OS) of MM patients.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, ultimately, most patients inevitably face the outcome of Relapse and drug resistance. Stem cell-like memory T cell (T&lt;sub&gt;SCM&lt;/sub&gt;) cells are a population of long-lived memory T cells with the capacity for self-renewal and differentiation.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; However, T&lt;sub&gt;SCM&lt;/sub&gt; cells are extremely low in proportion, and current technology still does not allow for easy access to sufficient quantities of T&lt;sub&gt;SCM&lt;/sub&gt; cells.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Currently, the therapeutic strategy of CAR-T&lt;sub&gt;SCM&lt;/sub&gt; has been actively pursued in solid tumours, but it is still rare in MM.&lt;/p&gt;&lt;p&gt;We first investigated the quantity and function of bone marrow T&lt;sub&gt;SCM&lt;/sub&gt; cells in MM patients with flow cytometry (FCM). We chose ‘CD3&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; events/CD3&lt;sup&gt;+&lt;/sup&gt;T events’ and ‘CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; events/CD8&lt;sup&gt;+&lt;/sup&gt;T events’ to show the percentage of T&lt;sub&gt;SCM&lt;/sub&gt; and to ensure the comparability of the statistics results. The results revealed that the percentage of CD3&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells was significantly reduced in the newly diagnosed MM (NDMM) compared to both the health control (HC) (0.51 ± 0.31% vs. 0.98 ± 0.39%) and the complete response (CR) (0.51 ± 0.31% vs. 0.92 ± 0.54%) (&lt;i&gt;p &lt;/i&gt;&lt;  .0001, &lt;i&gt;p &lt;/i&gt;= .0005). The percentage of CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells, which was reduced in the NDMM compared to both the HC (0.41 ± 0.28% vs. 0.97 ± 0.40%) and the CR (0.41 ± 0.28% vs. 0.61 ± 0.36%) (&lt;i&gt;p &lt;/i&gt;&lt;  .0001, &lt;i&gt;p &lt;/i&gt;= .0132) (Figure S1A,B).&lt;/p&gt;&lt;p&gt;Then, we found that the expression levels of Perforin and Granzyme B were significantly higher in CD3&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells compared to CD3&lt;sup&gt;+&lt;/sup&gt;T cells (42.26 ± 3.69% vs. 15.32 ± 2.75%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001; 57.18 ± 6.38% vs. 21.56 ± 3.38%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001); similarly, higher in CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sub&gt;SCM&lt;/sub&gt; cells than in CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T cells (47.77 ± 3.18% vs. 18.37 ± 3.89%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001; 50.30 ± 4.12% vs. 28.84 ± 3.49%, &lt;i&gt;p &lt;/i&gt;&lt;  .0001) (Figure S1C).&lt;/p&gt;&lt;p&gt;Afterwards, we took the bone marrow from MM patients who were candidates for B-cell maturation antigen (BCMA)-CART treatment. After aspiration, part of the bone marrow from these patients was used for their own clinical treatments and the rest was used in this experiment. Then we induced the expansion of T&lt;sub&gt;SCM&lt;/sub&gt; cells in vitro and FCM was used to detect the number and function of T&lt;sub&gt;SCM&lt;/sub&gt; cells (Figure 1A).&lt;/p&gt;&lt;p&gt;It has been demonstrated that MEK1/2 inhibition (MEKi) can be used to perform T&lt;sub&gt;SC","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554477","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":"Vascularised organoids: Recent advances and applications in cancer research","authors":"Rui Zhou,&nbsp;Dagmar Brislinger,&nbsp;Julia Fuchs,&nbsp;Alicia Lyons,&nbsp;Sonja Langthaler,&nbsp;Charlotte A. E. Hauser,&nbsp;Christian Baumgartner","doi":"10.1002/ctm2.70258","DOIUrl":"https://doi.org/10.1002/ctm2.70258","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;Organoids are three-dimensional (3D) cellular models designed to replicate human tissues and organs while preserving their physiological complexity and functionality. Among these, vascularised organoids represent a groundbreaking advancement in 3D tissue engineering, incorporating vascular networks into engineered tissues to more accurately mimic the in vivo tumour microenvironment. These models offer significantly improved physiological relevance compared to conventional two-dimensional cultures or animal models, positioning them as invaluable tools in cancer research. Despite their potential, the rapid proliferation of techniques and materials for developing vascularised organoids presents challenges for researchers navigating this dynamic field. This systematic review provides a comprehensive examination of methodologies for fabricating vascularised organoids, with a focus on strategies that enhance vascularisation and support organoid growth. It critically evaluates the materials used, emphasising those that effectively mimic the extracellular matrix and facilitate vascular network formation. Key advancements in engineered organoids models are highlighted, emphasising their potential for studying interactions between vasculature and cancer cells, conducting drug screening, and understanding cytokine regulation. In summary, this review provides an in-depth overview of the current landscape of vascularised organoid fabrication and functionality, addressing challenges and opportunities within the field. A detailed understanding of the scope and future trajectories is essential for advancing organoid development and expanding their applications in both basic cancer research and clinical practice.&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;Comparative analysis: Evaluation of organoids, animal models, and 2D models, highlighting their respective strengths and limitations in replicating physiological conditions and studying disease processes.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Vascularisation techniques: Comparative evaluation of vascularised organoid fabrication methods, emphasising their efficiency, scalability and ability to replicate physiological vascular networks.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Material selection: Thorough evaluation of materials for vascularised organoid culture system, focusing on those that effectively mimic the extracellular matrix and support vascular network formation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Applications: Overview of organoid applications in basic cancer research and clinical settings, with an emphasis on their potential in drug discovery, disease modelling and exploring complex biological p","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554478","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":"BRAFV600E-PROTAC versus inhibitors in melanoma cells: Deep transcriptomic characterisation","authors":"Solomon O. Alhassan,&nbsp;Zakaria Y. Abd Elmageed,&nbsp;Youssef Errami,&nbsp;Guangdi Wang,&nbsp;Joe A. Abi-Rached,&nbsp;Emad Kandil,&nbsp;Mourad Zerfaoui","doi":"10.1002/ctm2.70251","DOIUrl":"https://doi.org/10.1002/ctm2.70251","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study compares the suppression of Mitogen-activated protein kinase (MAPK) signalling and early resistance potential between a proteolysis-targeting chimera (PROTAC) and inhibitors targeting BRAF^V600E.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a detailed in silico analysis of the transcriptomic landscape of the A375 melanoma cell line treated with a PROTAC and BRAF^V600E inhibitors from RNA sequencing data. The study assessed gene dysregulation, MAPK and Phosphoinositide-3-kinase (PI3K/AKT) pathway inhibition, and cell survival. Key genes uniquely dysregulated by PROTAC treatment were validated by qPCR. Furthermore, analysis was performed to evaluate dedifferentiation and early resistance signatures to understand melanoma drug-induced plasticity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PROTAC-treated cells showed significantly lower MAPK pathway activity, strong cell cycle arrest and elevated apoptotic gene expression compared to inhibitor-treated cells, with no effect on the PI3K/AKT pathway. A high microphtalmia-associated transcription factor (MITF)/Tyrosine-Protein Kinase Receptor (AXL) ratio in PROTAC-treated cells indicated reduced early drug resistance. BRAF degradation induced a melanocytic-transitory phenotype. Although PROTAC and inhibitor treatments caused overlapping transcriptomic changes, key differences were observed. PROTAC treatment enriched processes such as epithelial‒mesenchymal transition, inflammatory responses, and Tumor necrosis factor-Alpha (TNF-α) and IL2/STAT5 signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>PROTAC-targeting BRAF^V600E demonstrates enhanced MAPK suppression, reduced early resistance and distinct transcriptional effects compared to traditional inhibitors. It represents a promising strategy for overcoming resistance in melanoma treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554488","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":"Long-term impact of obesity: Unraveling adipose epigenetic memory","authors":"Laura C. Hinte,&nbsp;Daniel Castellano-Castillo,&nbsp;Ferdinand von Meyenn","doi":"10.1002/ctm2.70254","DOIUrl":"https://doi.org/10.1002/ctm2.70254","url":null,"abstract":"&lt;p&gt;Obesity and its associated comorbidities represent a global health burden, with over 1 billion individuals currently living with obesity.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Thus, a primary objective in addressing the obesity pandemic, alongside preventative measures related to lifestyle and environmental factors, is achieving body weight reduction and long-term body weight stability. Therapeutic approaches range from dietary and lifestyle interventions to bariatric surgery and pharmacological treatments, such as incretin mimetics. However, short-term dietary and lifestyle interventions frequently do not achieve sustained weight loss and culminate in weight regain—the so-called yo‒yo effect. Even incretin mimetics (e.g., semaglutide and tirzepatide), which have demonstrated impressive efficacy in body weight reduction and improvement of metabolic health, fail to maintain weight stability following withdrawal in humans. The human body's tendency to defend increased body weight makes weight loss and maintenance challenging, potentially due to a phenomenon akin to a ‘metabolic memory’, reminiscent of the ‘legacy effect’ observed in diabetes. This metabolic memory may be mediated by a plethora of mechanisms such as structural physiological changes, alterations in synaptic plasticity,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; gut microbiome,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; immune system,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; vasculature,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; genetic contributions, and notably, epigenome, all of which warrant further investigation.&lt;/p&gt;&lt;p&gt;Epigenetic mechanisms are essential for cellular development, differentiation and identity maintenance, and they are increasingly implicated as crucial contributors to a memory of obesity.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Yet, it remained unresolved whether individual cells retain a metabolic memory of obesity and whether epigenetic mechanisms are involved in this. To address this question, we focused on the adipose tissue. Adipose tissue, a metabolically active organ, is heavily influenced by obesity and weight loss. As adipocytes are long-lived (approximately 10 years)&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; and non-dividing cells, they serve as an ideal model for studying epigenetic memory. Additionally, adipose tissue is easily accessible for human biopsies, enabling longitudinal studies not feasible for most other organs.&lt;/p&gt;&lt;p&gt;We collected human omental and abdominal subcutaneous adipose tissue biopsies from three European study centres in Germany and Sweden. Specifically, we obtained samples from individuals living with obesity but without diabetes, both before and 2 years after bariatric surgery (RYGB or sleeve gastrectomy), as well as from healthy normal-weight donors from the same centres. Only individuals who had lost at least 25% of their body mass index within 2 years were included. Using these biopsies, we performed single nucleus RNA sequencing (snRNA-seq) to obtain transcriptional data for each cell type in the adipose tissue. A comparative analy","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535839","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/ctm2.70268","DOIUrl":"https://doi.org/10.1002/ctm2.70268","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554690","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":"Proteogenomic characterisation of primary oral cancer unveils extracellular matrix remodelling and immunosuppressive microenvironment linked to lymph node metastasis","authors":"Yu Liu,&nbsp;Zhenyu Yang,&nbsp;Jingya Jane Pu,&nbsp;Jie Zhong,&nbsp;Ui-Soon Khoo,&nbsp;Yu-Xiong Su,&nbsp;Gao Zhang","doi":"10.1002/ctm2.70261","DOIUrl":"https://doi.org/10.1002/ctm2.70261","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Oral squamous cell carcinoma (OSCC) is an increasingly prevalent malignancy worldwide. This study aims to understand molecular alterations associated with lymph node metastasis of OSCC in order to improve treatment strategies. We analysed a cohort of 46 patients with primary OSCC, including 10 with lymph node metastasis and 36 without. Using a comprehensive multi-omics approach – encompassing genomic, transcriptomic, proteomic, epigenetic, single-cell, and spatial analyses – we integrated data to delineate the molecular landscape of OSCC in the context of lymph node metastasis. Our genomic analysis identified significant mutations in key genes within the MAPK, TGF-β and WNT signalling pathways, which are essential for tumour development. The proteogenomic analysis highlighted pathways critical for lymph node dissemination and factors contributing to an immunosuppressive tumour microenvironment. Elevated levels of POSTN were found to reorganise the extracellular matrix (ECM), interact with TGF-β, disrupt cell cycle regulation and suppress the immune response by reducing VCAM1 activity. Integrated analyses of single-cell and spatial transcriptome data revealed that cancer-associated fibroblasts (CAFs) secrete TGF-β1/2, promoting cancer cell metastasis through epithelial–mesenchymal transition (EMT). Our integrated multi-omics analysis provides a detailed understanding of molecular mechanisms driving lymph node metastasis of OSCC. These insights could lead to more precise diagnostics and targeted treatments.</p>\u0000 \u0000 <p>This article is protected by copyright. All rights reserved</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554691","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":"SH3GL1-activated FTH1 inhibits ferroptosis and confers doxorubicin resistance in diffuse large B-cell lymphoma","authors":"Zi-Wen Duan,&nbsp;Wei-Ting Wang,&nbsp;Yan Wang,&nbsp;Rong Wang,&nbsp;Wei Hua,&nbsp;Chun-Yu Shang,&nbsp;Rui Gao,&nbsp;Hao-Rui Shen,&nbsp;Yue Li,&nbsp;Jia-Zhu Wu,&nbsp;Hua Yin,&nbsp;Li Wang,&nbsp;Jian-Yong Li,&nbsp;Wei Xu,&nbsp;Jin-Hua Liang","doi":"10.1002/ctm2.70246","DOIUrl":"https://doi.org/10.1002/ctm2.70246","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diffuse large B-cell lymphoma (DLBCL) is predominant subtype of non-Hodgkin lymphoma and can be effectively treated. Nevertheless, a subset of patients experiences refractory or relapsed disease, highlighting the need for new therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Depmap database based on CRISPR/Cas9 knock out analysis was employed to identify the essential gene SH3GL1, which encodes endophilin A2, as crucial for the proliferation and survival of DLBCL cells. Immunohistochemistry (IHC) staining was performed on the 126 paraffin-embedded clinical DLBCL samples to investigate the association between SH3GL1 expression levels and the prognosis. To investigate the specific mechanism modulated by SH3GL1 in the progression of DLBCL, an integrative approach was employed. This approach combined high-throughput sequencing technologies, such as Deep-DIA and LC-MS, with functional validation techniques, including CRISPR/Cas9 gene editing, xenograft models, and molecular pathway analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our study found that high expression levels of SH3GL1 correlate with poor prognosis in a cohort of 126 newly diagnosed DLBCL patients, underscoring its significance in disease progression. Mechanistically, we found that SH3GL1 deficiency triggers ferritin heavy chain 1 (FTH1)-mediated ferroptosis, specifically ferritinophagy-induced ferroptosis, in DLBCL cells. Additionally, high expression of SH3GL1 suppresses doxorubicin-induced ferroptosis. Cancer cells' resistance to conventional therapies is associated with increased sensitivity to ferroptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings emphasise SH3GL1 as a promising prognostic biomarker and a potential therapeutic target in DLBCL, offering new avenues for treatment strategies aimed at overcoming drug resistance and improving patients' outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Elevated SH3GL1 expression in DLBCL patients was associated with a negative prognosis.</li>\u0000 \u0000 <li>SH3GL1 plays a crucial role in promoting DLBCL cell survival through the regulation of FTH1-mediated ferroptosis and doxorubicin resistance.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554692","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}