{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70585","DOIUrl":"https://doi.org/10.1002/ctm2.70585","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891093","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}
Lu Chen, Chunluan Yuan, Teng Yu, Kaiyuan Hui, Xiuming Li, Xiaozhu Shen, Xiaodong Jiang, Bin Liu
<div> <section> <h3> Background</h3> <p>Colorectal adenocarcinoma (COAD) cells exploit stress-adaptation programs, such as the unfolded protein response (UPR), to survive in hostile tumour microenvironments. However, the role of specific E3 ubiquitin ligases in regulating these survival pathways remains poorly understood. We investigated Ring Finger Protein 39 (RNF39), an E3 ligase previously implicated in immune signalling, as a potential regulator of COAD progression.</p> </section> <section> <h3> Methods</h3> <p>We analyzed RNF39 expression using public transcriptomic datasets (TCGA, GEO) and a clinical COAD cohort via immunohistochemistry. Functional roles were assessed in COAD cell lines using shRNA knockdown, CRISPR/Cas9 knockout, and overexpression systems. In vitro assays (proliferation, invasion, colony formation) and in vivo xenograft models were employed. Mechanistic investigations included co-immunoprecipitation, ubiquitination assays, chromatin immunoprecipitation, and luciferase reporter assays to delineate the MEF2D-RNF39-RINT1 axis.</p> </section> <section> <h3> Results</h3> <p>RNF39 was aberrantly upregulated in COAD tissues, and its high expression correlated with poor patient survival. We identified the transcription factor MEF2D as a direct activator of RNF39. Functionally, RNF39 promoted COAD cell proliferation and invasion in vitro and tumour growth in vivo, dependent on its E3 ligase activity. Mechanistically, RNF39 directly interacted with, polyubiquitinated (K48-linked), and promoted the proteasomal degradation of RAD50-interacting protein 1 (RINT1). Consequently, RNF39 depletion stabilized RINT1, amplified the UPR and CHOP expression, and sensitized cells to ER stress-induced apoptosis. Crucially, the anti-tumour phenotypes of RNF39 loss were partially reversed by simultaneous RINT1 knockdown.</p> </section> <section> <h3> Conclusion</h3> <p>RNF39 acts as a pro-tumorigenic E3 ligase in COAD by driving the degradation of RINT1, thereby suppressing ER stress-induced apoptosis and promoting malignant progression. Our findings delineate a novel MEF2D-RNF39-RINT1 signalling axis that governs tumour cell adaptation to stress. Targeting RNF39 could represent a promising therapeutic strategy to overcome stress resistance in COAD.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>RNF39 is identified as an oncogenic E3 ubiquitin ligase that is upregulated in col
{"title":"RNF39 promotes colorectal cancer progression by driving RINT1 degradation and suppressing ER stress-induced apoptosis","authors":"Lu Chen, Chunluan Yuan, Teng Yu, Kaiyuan Hui, Xiuming Li, Xiaozhu Shen, Xiaodong Jiang, Bin Liu","doi":"10.1002/ctm2.70577","DOIUrl":"10.1002/ctm2.70577","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal adenocarcinoma (COAD) cells exploit stress-adaptation programs, such as the unfolded protein response (UPR), to survive in hostile tumour microenvironments. However, the role of specific E3 ubiquitin ligases in regulating these survival pathways remains poorly understood. We investigated Ring Finger Protein 39 (RNF39), an E3 ligase previously implicated in immune signalling, as a potential regulator of COAD progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed RNF39 expression using public transcriptomic datasets (TCGA, GEO) and a clinical COAD cohort via immunohistochemistry. Functional roles were assessed in COAD cell lines using shRNA knockdown, CRISPR/Cas9 knockout, and overexpression systems. In vitro assays (proliferation, invasion, colony formation) and in vivo xenograft models were employed. Mechanistic investigations included co-immunoprecipitation, ubiquitination assays, chromatin immunoprecipitation, and luciferase reporter assays to delineate the MEF2D-RNF39-RINT1 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RNF39 was aberrantly upregulated in COAD tissues, and its high expression correlated with poor patient survival. We identified the transcription factor MEF2D as a direct activator of RNF39. Functionally, RNF39 promoted COAD cell proliferation and invasion in vitro and tumour growth in vivo, dependent on its E3 ligase activity. Mechanistically, RNF39 directly interacted with, polyubiquitinated (K48-linked), and promoted the proteasomal degradation of RAD50-interacting protein 1 (RINT1). Consequently, RNF39 depletion stabilized RINT1, amplified the UPR and CHOP expression, and sensitized cells to ER stress-induced apoptosis. Crucially, the anti-tumour phenotypes of RNF39 loss were partially reversed by simultaneous RINT1 knockdown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>RNF39 acts as a pro-tumorigenic E3 ligase in COAD by driving the degradation of RINT1, thereby suppressing ER stress-induced apoptosis and promoting malignant progression. Our findings delineate a novel MEF2D-RNF39-RINT1 signalling axis that governs tumour cell adaptation to stress. Targeting RNF39 could represent a promising therapeutic strategy to overcome stress resistance in COAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>RNF39 is identified as an oncogenic E3 ubiquitin ligase that is upregulated in col","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848857","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}
Laura E. Kane, Croí E. Buckley, Rebecca M. O'Brien, Meghana S. Menon, Aisling B. Heeran, Xiaofei Yin, Timothy S. Nugent, Noel E. Donlon, John V Reynolds, Adnan Hafeez, Diarmuid S. O'Ríordáin, Robert A. Hannon, Paul Neary, Reza Kalbassi, Brian J. Mehigan, Paul H. McCormick, Cara Dunne, John O. Larkin, Lorraine Brennan, Michael E. Kelly, Jacintha O'Sullivan, Niamh Lynam-Lennon
<p>Dear Editor,</p><p>Rectal cancer (RC) incidence is rising, particularly in individuals < 50 years, who present with aggressive, treatment-refractory tumours.<span><sup>1</sup></span> Resistance to neoadjuvant treatment (neo-tx) is a significant problem, with no biomarkers of response currently in use. Tumours of similar clinical characteristics can have vastly different responses to neo-tx, suggesting the dichotomy in response is due to differences in the tumour molecular environment. Alterations in mitochondrial function and energy metabolism play a role in the pathogenesis of gastrointestinal cancers,<span><sup>2, 3</sup></span> implicating the metabolome as a potential untapped source of predictive biomarkers. To address this unmet need, we performed multi-omic analysis of metabolomic and transcriptomic profiles from normal, non-cancer rectal tissue and pre-treatment RC biopsies (Supporting Information) to identify alterations associated with the pathogenesis of RC.</p><p>Liquid chromatography-mass spectrometry revealed 29 metabolites significantly altered in RC tissue (<i>n </i>= 32) compared to non-cancer rectal tissue (<i>n </i>= 20) (Figure 1A). Pathway analysis uncovered 65 upregulated and four downregulated pathways significantly associated with altered metabolites (Figure 1B). Most altered metabolites were lipid molecules or mediators of lipid metabolism, suggesting that remodelling of lipid metabolism is a feature of RC. Diacyl phosphatidylcholines (PCs) are important mediators of lipid metabolism, supporting other studies highlighting a role for choline metabolism and lipid remodelling in tumourigenesis.<span><sup>4</sup></span> SM C18:0 and SM (OH) C22:1 are sphingolipids, important structural lipid components of biological membranes, which support the physiological function of the colon and are deregulated in RC.<span><sup>5</sup></span> Interestingly, cancer cells hydrolyse sphingomyelin to maintain production of PCs,<span><sup>4</sup></span> suggesting a mechanism for the concomitant increase in PCs and decrease in sphingomyelins demonstrated in RC here.</p><p>Real-time metabolic analysis demonstrated that (Figure 1C)OCR rates and OCR/ECAR ratios were significantly decreased in RC compared to non-cancer rectal tissue, highlighting metabolic remodelling in RC. Inhibition of mitochondrial metabolism results in accelerated turnover of PCs in neuronal cells,<span><sup>6</sup></span> suggesting a mechanism underlying the altered choline metabolism demonstrated in RC.</p><p>Transcriptomics revealed 2337 genes differentially expressed between RC (<i>n </i>= 31) and non-cancer rectal tissue (<i>n </i>= 28) (Figure 1D). Pathway analysis revealed 41 upregulated and seven downregulated pathways significantly associated with altered genes (Figure 1E). Interestingly, several of the most altered genes play roles in mitochondrial respiration. <i>ND2</i>, <i>ND3</i> and <i>ND5</i> encode subunits of the NADH dehydrogenase enzyme, a crucial
亲爱的编辑，直肠癌（RC）的发病率正在上升，特别是在50岁以上的个体中，他们表现出侵袭性，难治性肿瘤对新辅助治疗（neo-tx）的耐药是一个重要的问题，目前还没有生物标志物的反应。临床特征相似的肿瘤可能对neo-tx有截然不同的反应，这表明反应的二分法是由于肿瘤分子环境的差异。线粒体功能和能量代谢的改变在胃肠道癌症的发病机制中发挥作用，2,3暗示代谢组是一种潜在的未开发的预测性生物标志物来源。为了解决这一未满足的需求，我们对正常、非癌性直肠组织和治疗前直肠癌活检的代谢组学和转录组学进行了多组学分析，以确定与直肠癌发病机制相关的改变。液相色谱-质谱分析显示，与非癌直肠组织（n = 20）相比，癌组织中有29种代谢物显著改变（n = 32）（图1A）。通路分析发现65条上调通路和4条下调通路与代谢产物改变显著相关（图1B）。大多数改变的代谢物是脂质分子或脂质代谢介质，这表明脂质代谢的重塑是RC的一个特征。二酰基磷脂酰胆碱（PCs）是脂质代谢的重要介质，支持其他研究强调胆碱代谢和脂质重塑在肿瘤发生中的作用SM C18:0和SM (OH) C22:1是鞘脂，是生物膜的重要结构脂质成分，支持结肠的生理功能，在RC中不受调节。有趣的是，癌细胞水解鞘磷脂以维持pc的产生，这表明在RC中证明了pc同时增加和鞘磷脂减少的机制。实时代谢分析显示（图1C），与非癌性直肠组织相比，癌性直肠组织的OCR率和OCR/ECAR比值显著降低，突出了癌性直肠组织的代谢重塑。线粒体代谢的抑制导致神经元细胞中pc的更新加速，6这表明在RC中证实了胆碱代谢改变的机制。转录组学显示，有2337个基因在直肠癌组织（n = 31）和非癌直肠组织（n = 28）之间存在差异表达（图1D）。通路分析显示41条上调通路和7条下调通路与基因改变显著相关（图1E）。有趣的是，一些改变最多的基因在线粒体呼吸中起作用。ND2， ND3和ND5编码NADH脱氢酶的亚基，NADH脱氢酶是电子传递链的关键组成部分，支持在RC组织中显示的改变的OCR。在治疗前的RC活检中，改变的代谢物与OCR、ECAR、OCR/ECAR比值以及几个临床变量（包括改进的Ryan肿瘤反应评分（TRS））有显著相关性（TRS1 =完全缓解，TRS1 =接近完全缓解，TRS2 =部分缓解）（图2A）。两种代谢物与TRS显著相关：血清素和lysoPC a C16:1（图2B）。无监督分层聚类在TRS2中显示出良好的分组，TRS0和TRS1之间几乎没有区别，表明两者之间的表达谱相似（图2C）。只有lysoPC a C16:1与临床变量有显著相关性（图2D）。SLC6A4在CRC组织中的表达，其转录5 -羟色胺，对无复发生存无显著影响（图2E），而SLC6A4的低表达导致进展后生存显著恶化（图2F）。5 -羟色胺可增强结肠癌患者的放射敏感性，7提示TRS2患者血清素降低是neo-tx耐药的机制之一。改变的基因与几个临床变量有显著相关性（图3A）。RPL30和CXCL14在TRS2中显著上调，而SNORA81、SNORD50A、LCN2和SNORA64在TRS2中与TRS0相比显著下调（图3B）。RPL30的表达增加与癌基因MYC的扩增有关，从而促进细胞毒性治疗的耐药性在一些癌症中，SNORD50A的缺失与较差的生存结果相关有趣的是，SNORD50A结合并抑制癌基因KRAS， SNORD50A的耗尽导致MAPK级联的激活，9参与肿瘤对治疗的耐药，10提示在RC中neo-tx耐药的潜在作用。基于基因表达的TRS分离得到了改进，TRS0和TRS2区分明显（图3C）。一些基因与临床变量有显著相关性（图3D）。低CXCL14表达与总体（图3E）和进展后生存期（图3F）明显较差相关。 高RPL30与较长的总生存期显著相关（图3G）；然而，它导致无复发生存（图3H）和进展后生存（图3I）显著恶化，这与TRS2患者的高RPL30一致。同样，低LCN2表达与较差的总生存率相关（图3J）。改变的基因和代谢物被整合到一个8个特征的多组学生物标志物面板中。由于没有匹配的TRS3患者转录组数据，只有TRS0 （n = 3）、TRS1 （n = 6）和TRS2 （n = 5）组可以纳入最终分析。TRS0和TRS2分别使用这8个特征进行聚类，TRS1分布在它们之间（图4A）。主成分分析显示了类似的模式，血清素、SNORA64、SNORD50A、SNORA81、RPL30和CXCL14对组分离的贡献最大（图4B）。单独检查各特征的表达情况，TRS0和TRS2的单独特征表达水平较高，而TRS1位于TRS0和TRS2的范围内（图4C）。留一交叉验证表明，TRS0与TRS1/TRS2的区别较差（曲线下面积[AUC] = 0.273，灵敏度= 0%，特异性= 54.5%），可能是由于组间样本的不平衡（TRS0 = 3, TRS1/TRS2 = 11），因此不能准确地代表这些组间面板的性能（图4D）。与TRS2相比，TRS0的分类准确率要高得多（AUC = 0.933，灵敏度= 100%，特异性= 80%），这与观察到的不同表达谱一致（图4B，C）。最后，在该试点队列中，TRS0/TRS1与TRS2表现出完美的分类（AUC = 1, Sensitivity = 100%, Specificity = 100%），表明总体而言，TRS2患者的表达谱与TRS0和TRS1不同，两者之间的关系更为密切（图4D）。在一个试点队列中，我们证明直肠肿瘤具有代谢和转录组重塑，强调脂质代谢改变是直肠肿瘤的共同特征，提出了一种新的治疗靶向方法。我们还确定了一个新的多组学8-生物标志物面板，在代表全TRS谱的独立队列验证后，有潜力作为neo-tx病理反应的预测标志，以改善患者分层。劳拉e凯恩：数据策展，正式分析和写作-原始草案。Croí E. Buckley：调查，数据管理和形式分析。丽贝卡·M. o .布莱恩：数据管理和资源。Meghana S. Menon：数据管理和资源。Aisling B. Heeran：数据管理和资源。尹晓飞：调查与形式分析。Timothy S. Nugent：临床样本和临床数据。Noel E. Donlon：临床样本和临床数据。约翰·v·雷诺兹：资源。Adnan Hafeez：临床样本。Diarmuid S. O.R-ordáin：临床样本。Robert A. Hannon：临床样本。Paul Neary：临床样本。Reza Kalbassi：临床样本。Brian J. Mehigan：临床样本。Paul H. McCormick：临床样本。卡拉·邓恩：临床样本。John O. Larkin：临床样本。洛林·布伦南：形式分析和写作——审查和编辑。迈克尔E.凯利：临床样本，临床数据和写作-审查和编辑。贾辛塔O.沙利文：概念，监督和写作-审查和编辑。概念化、监督、资金获取、写作。原稿和写作-审查和编辑。作者声明无利益冲突。这项研究由卫生研究委员会（爱尔兰）资助，资助号：EIA-2017-020。我们也感谢SFI研究基础设施计划下的综合分子分析平台（CMAP）的资助，参考编号：18/RI/5702。勒。凯恩得到了爱尔兰研究基
{"title":"A multi-omic biomarker signature in pre-treatment rectal tumours stratifies patients with different pathological responses to neoadjuvant treatment","authors":"Laura E. Kane, Croí E. Buckley, Rebecca M. O'Brien, Meghana S. Menon, Aisling B. Heeran, Xiaofei Yin, Timothy S. Nugent, Noel E. Donlon, John V Reynolds, Adnan Hafeez, Diarmuid S. O'Ríordáin, Robert A. Hannon, Paul Neary, Reza Kalbassi, Brian J. Mehigan, Paul H. McCormick, Cara Dunne, John O. Larkin, Lorraine Brennan, Michael E. Kelly, Jacintha O'Sullivan, Niamh Lynam-Lennon","doi":"10.1002/ctm2.70576","DOIUrl":"10.1002/ctm2.70576","url":null,"abstract":"<p>Dear Editor,</p><p>Rectal cancer (RC) incidence is rising, particularly in individuals < 50 years, who present with aggressive, treatment-refractory tumours.<span><sup>1</sup></span> Resistance to neoadjuvant treatment (neo-tx) is a significant problem, with no biomarkers of response currently in use. Tumours of similar clinical characteristics can have vastly different responses to neo-tx, suggesting the dichotomy in response is due to differences in the tumour molecular environment. Alterations in mitochondrial function and energy metabolism play a role in the pathogenesis of gastrointestinal cancers,<span><sup>2, 3</sup></span> implicating the metabolome as a potential untapped source of predictive biomarkers. To address this unmet need, we performed multi-omic analysis of metabolomic and transcriptomic profiles from normal, non-cancer rectal tissue and pre-treatment RC biopsies (Supporting Information) to identify alterations associated with the pathogenesis of RC.</p><p>Liquid chromatography-mass spectrometry revealed 29 metabolites significantly altered in RC tissue (<i>n </i>= 32) compared to non-cancer rectal tissue (<i>n </i>= 20) (Figure 1A). Pathway analysis uncovered 65 upregulated and four downregulated pathways significantly associated with altered metabolites (Figure 1B). Most altered metabolites were lipid molecules or mediators of lipid metabolism, suggesting that remodelling of lipid metabolism is a feature of RC. Diacyl phosphatidylcholines (PCs) are important mediators of lipid metabolism, supporting other studies highlighting a role for choline metabolism and lipid remodelling in tumourigenesis.<span><sup>4</sup></span> SM C18:0 and SM (OH) C22:1 are sphingolipids, important structural lipid components of biological membranes, which support the physiological function of the colon and are deregulated in RC.<span><sup>5</sup></span> Interestingly, cancer cells hydrolyse sphingomyelin to maintain production of PCs,<span><sup>4</sup></span> suggesting a mechanism for the concomitant increase in PCs and decrease in sphingomyelins demonstrated in RC here.</p><p>Real-time metabolic analysis demonstrated that (Figure 1C)OCR rates and OCR/ECAR ratios were significantly decreased in RC compared to non-cancer rectal tissue, highlighting metabolic remodelling in RC. Inhibition of mitochondrial metabolism results in accelerated turnover of PCs in neuronal cells,<span><sup>6</sup></span> suggesting a mechanism underlying the altered choline metabolism demonstrated in RC.</p><p>Transcriptomics revealed 2337 genes differentially expressed between RC (<i>n </i>= 31) and non-cancer rectal tissue (<i>n </i>= 28) (Figure 1D). Pathway analysis revealed 41 upregulated and seven downregulated pathways significantly associated with altered genes (Figure 1E). Interestingly, several of the most altered genes play roles in mitochondrial respiration. <i>ND2</i>, <i>ND3</i> and <i>ND5</i> encode subunits of the NADH dehydrogenase enzyme, a crucial ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843204","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}
Acute respiratory distress syndrome (ARDS) frequently develops after cardiopulmonary bypass (CPB), with lung ischemia/reperfusion injury (LIRI) as a major contributing factor. However, the role of fatty acid-binding protein 4 (FABP4) in the pathogenesis of CPB-associated ARDS remains poorly understood.
Methods
Experimental LIRI models were established in vivo and in vitro to investigate the role of FABP4 in alveolar epithelial injury. Lipid droplets (LDs) accumulation, fatty acid (FA) metabolism, epithelial-mesenchymal transition (EMT), and alveolar epithelial barrier (AEB) integrity were assessed using molecular, cellular, and functional approaches. Pharmacological and genetic interventions were applied to evaluate the contribution of FABP4-mediated signaling pathways.
Results
LIRI induced autocrine FABP4 signaling in alveolar epithelial cells, leading to pronounced LDs accumulation and disruption of AEB integrity. FABP4 activation enhanced FA metabolism and promoted EMT, which played a critical role in epithelial barrier dysfunction. Mechanistically, FABP4 activated the p38 MAPK pathway, resulting in ULK1 phosphorylation, suppression of lipophagy, and subsequent LDs formation, thereby driving EMT. Inhibition of LDs accumulation effectively attenuated EMT and alleviated AEB disruption.
Conclusion
FABP4 serves as a key metabolic regulator linking lipid reprogramming to EMT and alveolar epithelial barrier disruption during LIRI. Targeting FABP4-mediated lipid metabolism may represent a promising therapeutic strategy for preventing ARDS following CPB.
Key points
LIRI induces autocrine FABP4 signaling in alveolar epithelial cells.
FABP4 promotes lipid droplets accumulation by inhibiting lipophagy through p38 MAPKULK1 signaling.
{"title":"FABP4-mediated lipid droplet accumulation drives epithelial–mesenchymal transition and aggravates alveolar epithelial barrier disruption","authors":"Zihao Shen, Yuanpu Qi, Mingyu Chu, Minchao Wu, Chen Feng, Xiangyu Li, Zhaoyang Liu, Linjie Si, Yongliang Wang, Jialin Zhang, Xiaoning Lu, Peng Lu","doi":"10.1002/ctm2.70563","DOIUrl":"10.1002/ctm2.70563","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute respiratory distress syndrome (ARDS) frequently develops after cardiopulmonary bypass (CPB), with lung ischemia/reperfusion injury (LIRI) as a major contributing factor. However, the role of fatty acid-binding protein 4 (FABP4) in the pathogenesis of CPB-associated ARDS remains poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Experimental LIRI models were established in vivo and in vitro to investigate the role of FABP4 in alveolar epithelial injury. Lipid droplets (LDs) accumulation, fatty acid (FA) metabolism, epithelial-mesenchymal transition (EMT), and alveolar epithelial barrier (AEB) integrity were assessed using molecular, cellular, and functional approaches. Pharmacological and genetic interventions were applied to evaluate the contribution of FABP4-mediated signaling pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LIRI induced autocrine FABP4 signaling in alveolar epithelial cells, leading to pronounced LDs accumulation and disruption of AEB integrity. FABP4 activation enhanced FA metabolism and promoted EMT, which played a critical role in epithelial barrier dysfunction. Mechanistically, FABP4 activated the p38 MAPK pathway, resulting in ULK1 phosphorylation, suppression of lipophagy, and subsequent LDs formation, thereby driving EMT. Inhibition of LDs accumulation effectively attenuated EMT and alleviated AEB disruption.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>FABP4 serves as a key metabolic regulator linking lipid reprogramming to EMT and alveolar epithelial barrier disruption during LIRI. Targeting FABP4-mediated lipid metabolism may represent a promising therapeutic strategy for preventing ARDS following CPB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>LIRI induces autocrine FABP4 signaling in alveolar epithelial cells.</li>\u0000 \u0000 <li>FABP4 promotes lipid droplets accumulation by inhibiting lipophagy through p38 MAPKULK1 signaling.</li>\u0000 \u0000 <li>FABP4-driven lipid metabolic reprogramming triggers EMT and disrupts alveolar epithelial barrier integrity.</li>\u0000 \u0000 <li>Targeting FABP4 or lipid droplets accumulation may offer therapeutic potential for CPB-associated ARDS.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843186","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}
Cristina Queralt, Cristina Moreta-Moraleda, Marta Costa, Ferran Grau-Leal, Jeannine Diesch, Carla Vendrell-Ayats, Eva Musulén, Roni H G Wright, Cristina Bugés, José Luis Manzano, Sara Cabrero-de las Heras, Johannes Zuber, Marcus Buschbeck, Sonia-V Forcales, Eva Martínez-Balibrea
<div> <section> <h3> Background</h3> <p>Colorectal cancer (CRC) remains a major global health concern, partly due to resistance to therapy and the lack of new effective treatments for advanced disease. The combination of 5-Fluorouracil (5FU, a thymidylate synthase inhibitor) and irinotecan (a topoisomerase 1 inhibitor) is widely used in first-line and subsequent treatments. This study aimed to identify novel therapeutic targets to enhance combinatorial therapy, improving treatment efficacy and durability of response.</p> </section> <section> <h3> Methods</h3> <p>We performed a loss-of-function screen using HT29 CRC cell line and a retroviral library containing 7296 shRNAs targeting 912 chromatin genes. Cells were then treated with 5FU and SN38 (the active metabolite of irinotecan) or left untreated for 4 weeks. Genes enriched in resistant clones were identified through next-generation sequencing. Amongst candidate genes, PARG was selected for functional validation.</p> </section> <section> <h3> Results</h3> <p>CRISPR/Cas9-mediated knockout (HT29 PARG-KO) resulted in increased global poly(ADP-ribosyl)ation after 5FU and SN38 treatment. PARG depletion led to reduced cell viability and increased apoptosis, particularly after 5FU exposure. Pharmacological PARG inhibition (PDD00017273) synergised with 5FU and SN38 across three CRC models (HT29, DLD1, HT115). In vivo, HT29 PARG-KO xenografts were more sensitive to 5FU. Immunohistochemical analysis of 170 CRC patient tumours revealed that positive PARG expression correlated with poor response to 5FU + Irinotecan, increased liver metastases, and worse long-term survival.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings highlight PARG as a promising therapeutic target for CRC, where its inhibition enhances the efficacy of standard chemotherapy.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>LOF screening identified PARG as a modulator of CRC response to FUIRI treatment.</li> <li>HT29 PARG-KO cells showed increased PAR, DNA damage, apoptosis, and 5FU sensitivity.</li> <li>Pharmacological PARG inhibition synergised with 5FU and SN38 in CRC cell lines.</li> <li>HT29 PARG-KO tumours exhibited increased sensitivity to 5FU treatment in vivo.</li> <li>PARG e
{"title":"Loss-of-function genetic screen unveils synergistic efficacy of PARG inhibition with combined 5-fluorouracil and irinotecan treatment in colorectal cancer","authors":"Cristina Queralt, Cristina Moreta-Moraleda, Marta Costa, Ferran Grau-Leal, Jeannine Diesch, Carla Vendrell-Ayats, Eva Musulén, Roni H G Wright, Cristina Bugés, José Luis Manzano, Sara Cabrero-de las Heras, Johannes Zuber, Marcus Buschbeck, Sonia-V Forcales, Eva Martínez-Balibrea","doi":"10.1002/ctm2.70543","DOIUrl":"10.1002/ctm2.70543","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal cancer (CRC) remains a major global health concern, partly due to resistance to therapy and the lack of new effective treatments for advanced disease. The combination of 5-Fluorouracil (5FU, a thymidylate synthase inhibitor) and irinotecan (a topoisomerase 1 inhibitor) is widely used in first-line and subsequent treatments. This study aimed to identify novel therapeutic targets to enhance combinatorial therapy, improving treatment efficacy and durability of response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a loss-of-function screen using HT29 CRC cell line and a retroviral library containing 7296 shRNAs targeting 912 chromatin genes. Cells were then treated with 5FU and SN38 (the active metabolite of irinotecan) or left untreated for 4 weeks. Genes enriched in resistant clones were identified through next-generation sequencing. Amongst candidate genes, PARG was selected for functional validation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CRISPR/Cas9-mediated knockout (HT29 PARG-KO) resulted in increased global poly(ADP-ribosyl)ation after 5FU and SN38 treatment. PARG depletion led to reduced cell viability and increased apoptosis, particularly after 5FU exposure. Pharmacological PARG inhibition (PDD00017273) synergised with 5FU and SN38 across three CRC models (HT29, DLD1, HT115). In vivo, HT29 PARG-KO xenografts were more sensitive to 5FU. Immunohistochemical analysis of 170 CRC patient tumours revealed that positive PARG expression correlated with poor response to 5FU + Irinotecan, increased liver metastases, and worse long-term survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings highlight PARG as a promising therapeutic target for CRC, where its inhibition enhances the efficacy of standard chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>LOF screening identified PARG as a modulator of CRC response to FUIRI treatment.</li>\u0000 \u0000 <li>HT29 PARG-KO cells showed increased PAR, DNA damage, apoptosis, and 5FU sensitivity.</li>\u0000 \u0000 <li>Pharmacological PARG inhibition synergised with 5FU and SN38 in CRC cell lines.</li>\u0000 \u0000 <li>HT29 PARG-KO tumours exhibited increased sensitivity to 5FU treatment in vivo.</li>\u0000 \u0000 <li>PARG e","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12741922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832909","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}
Juan F. Cardona, Hernando Santamaría-García, Agustín Ibáñez
<p>Cardona JF, Santamaría-García H, Ibáñez A. The biological burden of conflict across populations worldwide. <i>Clin Transl Med</i>. 2025;00:e70574. https://doi.org/10.1002/ctm2.70574</p><p>Contemporary societies are increasingly shaped by multilayered forms of interindividual and intergroup conflict that transcend traditional political or military boundaries.<span><sup>1, 2</sup></span> Violence, forced migration, environmental degradation, institutional fragility and widening social and political polarisation interact to generate complex forms of adversity that affect entire populations. These conditions carry profound consequences for mental and brain health, yet their biological impact remains insufficiently integrated into global health and policy agendas. Recent analyses show that even political polarisation itself now functions as a determinant of population health, shaping stress, trust, behaviour and risk perception.<span><sup>3</sup></span> Thus, understanding the biological burden of conflict requires a genuinely transdisciplinary perspective capable of linking neurobiological mechanisms with social determinants, ecological pressures and institutional dynamics.</p><p>Although classical armed conflicts persist, today's adversities extend beyond the battlefield. Many societies face recent escalating political polarisation, intergroup conflict, radicalisation, recurrent violence, institutional erosion, widening inequality and expanding illicit economies, including the resurgence of narcotrafficking and environmentally destructive extractive activities. High-income regions are not exempt; rising polarisation, mass shootings, hate crimes, digital extremism and climate-related displacement in the United States and Europe illustrate how conflict-like dynamics increasingly permeate daily life (Figure 1).</p><p>Globally, conflict-related adversity is intensifying. Countries such as Ukraine, Gaza, Sudan, Myanmar, Venezuela, Colombia and those across the Sahel experience interrelated crises involving displacement, food insecurity, environmental loss, organised violence and institutional collapse. As the United Nations recently stressed, ethnic violence and nationalist aggression continue to drive conflicts that displace millions and generate prolonged humanitarian emergencies.<span><sup>4</sup></span> Despite differences in political structure or geography, these contexts converge through shared mechanisms such as chronic adversity, disrupted community structures, cumulative stress exposure and the erosion of protective social and ecological systems.</p><p>Colombia provides a clear illustration of how contemporary conflicts can reconfigure themselves across time.<span><sup>5-7</sup></span> After the 2016 Peace Agreement, territorial fragmentation, the proliferation of armed groups, the expansion of illegal economies, and widespread narco-deforestation generated new cycles of violence and displacement. More than one million new displacements sinc
{"title":"The biological burden of conflict across populations worldwide","authors":"Juan F. Cardona, Hernando Santamaría-García, Agustín Ibáñez","doi":"10.1002/ctm2.70574","DOIUrl":"10.1002/ctm2.70574","url":null,"abstract":"<p>Cardona JF, Santamaría-García H, Ibáñez A. The biological burden of conflict across populations worldwide. <i>Clin Transl Med</i>. 2025;00:e70574. https://doi.org/10.1002/ctm2.70574</p><p>Contemporary societies are increasingly shaped by multilayered forms of interindividual and intergroup conflict that transcend traditional political or military boundaries.<span><sup>1, 2</sup></span> Violence, forced migration, environmental degradation, institutional fragility and widening social and political polarisation interact to generate complex forms of adversity that affect entire populations. These conditions carry profound consequences for mental and brain health, yet their biological impact remains insufficiently integrated into global health and policy agendas. Recent analyses show that even political polarisation itself now functions as a determinant of population health, shaping stress, trust, behaviour and risk perception.<span><sup>3</sup></span> Thus, understanding the biological burden of conflict requires a genuinely transdisciplinary perspective capable of linking neurobiological mechanisms with social determinants, ecological pressures and institutional dynamics.</p><p>Although classical armed conflicts persist, today's adversities extend beyond the battlefield. Many societies face recent escalating political polarisation, intergroup conflict, radicalisation, recurrent violence, institutional erosion, widening inequality and expanding illicit economies, including the resurgence of narcotrafficking and environmentally destructive extractive activities. High-income regions are not exempt; rising polarisation, mass shootings, hate crimes, digital extremism and climate-related displacement in the United States and Europe illustrate how conflict-like dynamics increasingly permeate daily life (Figure 1).</p><p>Globally, conflict-related adversity is intensifying. Countries such as Ukraine, Gaza, Sudan, Myanmar, Venezuela, Colombia and those across the Sahel experience interrelated crises involving displacement, food insecurity, environmental loss, organised violence and institutional collapse. As the United Nations recently stressed, ethnic violence and nationalist aggression continue to drive conflicts that displace millions and generate prolonged humanitarian emergencies.<span><sup>4</sup></span> Despite differences in political structure or geography, these contexts converge through shared mechanisms such as chronic adversity, disrupted community structures, cumulative stress exposure and the erosion of protective social and ecological systems.</p><p>Colombia provides a clear illustration of how contemporary conflicts can reconfigure themselves across time.<span><sup>5-7</sup></span> After the 2016 Peace Agreement, territorial fragmentation, the proliferation of armed groups, the expansion of illegal economies, and widespread narco-deforestation generated new cycles of violence and displacement. More than one million new displacements sinc","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843145","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}
<p>Aging trajectories vary widely across individuals, even under comparable biological and environmental pressures, yet most biomedical frameworks prioritize vulnerability over protection. This perspective proposes a shift towards identifying resilient expotype–phenotypes, defined by combinations of exposures and individual adaptive responses that support unexpectedly healthy aging. We propose multimodal aging clocks (focusing on delayed agers) to address resilience and its phenotypic and expotype contributions. Building on recent evidence from global exposome analyses<span><sup>1-4</sup></span>, multimodal aging clocks<span><sup>1, 5-8</sup></span> and neuroecological frameworks<span><sup>2, 9</sup></span>, we argue that resilience offers an essential dimension for precision brain health.</p><p>The exposome<span><sup>1, 10</sup></span> captures the totality of physical, social and sociopolitical exposures across the lifespan, exerting marked influences on biological, systemic and cognitive health. This multidimensional construct provides a foundation for defining expotypes<span><sup>11</sup></span>, the characteristic combinations of exposures that shape individual risk or protection<span><sup>12</sup></span>. Aging clocks (epigenetic clocks, proteomic or multi-omic clocks, brain clocks and biobehavioural clocks) quantify biological aging relative to chronological time, enabling direct assessment of how exposures modulate aging trajectories. These tools reveal that diverse exposures, from pollution and temperature peaks to structural inequalities and political instability, accelerate biological aging,<span><sup>1, 2, 6</sup></span> whereas enriching environments, cognitive stimulation and social cohesion may delay it. Together, they provide a framework for evaluating how cumulative exposures influence aging across datasets, populations and biological systems<span><sup>12, 13</sup></span>. Thus, the exposome and aging clocks may jointly enable a more mechanistic assessments of how protective and adverse exposures shape biological aging across systems.</p><p>Our recent <i>Nature Medicine</i> study illustrates how biobehavioural age gaps (BBAGs) – the discrepancy between predicted age from protective/risk factors and chronological age – capture delayed or accelerated aging across 40 countries<span><sup>1</sup></span>. BBAGs were estimated using a Gradient Boosting Regressor with 10-fold cross-validation to predict age from biobehavioural factors (risk and protective) in >160 000 participants. The age gap was computed as predicted minus chronological age, with negative values indicating delayed and positive values indicating accelerated aging. To correct regression-to-the-mean, gaps were residualized against chronological age using coefficients from the training set and applied to the test set. Delayed BBAGs were linked to favourable exposomes: cleaner air, inclusive migration contexts, structural and gender equality, and democratic stability. Th
{"title":"Expotype–phenotype resilience and multimodal aging clocks","authors":"Hernan Hernandez, Agustin Ibanez","doi":"10.1002/ctm2.70558","DOIUrl":"10.1002/ctm2.70558","url":null,"abstract":"<p>Aging trajectories vary widely across individuals, even under comparable biological and environmental pressures, yet most biomedical frameworks prioritize vulnerability over protection. This perspective proposes a shift towards identifying resilient expotype–phenotypes, defined by combinations of exposures and individual adaptive responses that support unexpectedly healthy aging. We propose multimodal aging clocks (focusing on delayed agers) to address resilience and its phenotypic and expotype contributions. Building on recent evidence from global exposome analyses<span><sup>1-4</sup></span>, multimodal aging clocks<span><sup>1, 5-8</sup></span> and neuroecological frameworks<span><sup>2, 9</sup></span>, we argue that resilience offers an essential dimension for precision brain health.</p><p>The exposome<span><sup>1, 10</sup></span> captures the totality of physical, social and sociopolitical exposures across the lifespan, exerting marked influences on biological, systemic and cognitive health. This multidimensional construct provides a foundation for defining expotypes<span><sup>11</sup></span>, the characteristic combinations of exposures that shape individual risk or protection<span><sup>12</sup></span>. Aging clocks (epigenetic clocks, proteomic or multi-omic clocks, brain clocks and biobehavioural clocks) quantify biological aging relative to chronological time, enabling direct assessment of how exposures modulate aging trajectories. These tools reveal that diverse exposures, from pollution and temperature peaks to structural inequalities and political instability, accelerate biological aging,<span><sup>1, 2, 6</sup></span> whereas enriching environments, cognitive stimulation and social cohesion may delay it. Together, they provide a framework for evaluating how cumulative exposures influence aging across datasets, populations and biological systems<span><sup>12, 13</sup></span>. Thus, the exposome and aging clocks may jointly enable a more mechanistic assessments of how protective and adverse exposures shape biological aging across systems.</p><p>Our recent <i>Nature Medicine</i> study illustrates how biobehavioural age gaps (BBAGs) – the discrepancy between predicted age from protective/risk factors and chronological age – capture delayed or accelerated aging across 40 countries<span><sup>1</sup></span>. BBAGs were estimated using a Gradient Boosting Regressor with 10-fold cross-validation to predict age from biobehavioural factors (risk and protective) in >160 000 participants. The age gap was computed as predicted minus chronological age, with negative values indicating delayed and positive values indicating accelerated aging. To correct regression-to-the-mean, gaps were residualized against chronological age using coefficients from the training set and applied to the test set. Delayed BBAGs were linked to favourable exposomes: cleaner air, inclusive migration contexts, structural and gender equality, and democratic stability. Th","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843211","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}
Zijian Liu, Jingsheng Yuan, Shitong Su, Jiaqi Han, Ni Zeng, Yuhan Ma, Nianyong Chen, Tao Lv
<div> <section> <h3> Background</h3> <p>Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.</p> </section> <section> <h3> Methods</h3> <p>Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot.</p> </section> <section> <h3> Results</h3> <p>AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10–lactate–LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models.</p> </section> <section> <h3> Conclusions</h3> <p>These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA–lenvatinib therapy.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells.</li> <li>AKR1B10 undergoes AARS1-mediated lact
{"title":"AARS1-mediated AKR1B10 lactylation stabilizes an aerobic glycolysis-positive feedback loop to drive lenvatinib resistance in hepatocellular carcinoma","authors":"Zijian Liu, Jingsheng Yuan, Shitong Su, Jiaqi Han, Ni Zeng, Yuhan Ma, Nianyong Chen, Tao Lv","doi":"10.1002/ctm2.70561","DOIUrl":"10.1002/ctm2.70561","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10–lactate–LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA–lenvatinib therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells.</li>\u0000 \u0000 <li>AKR1B10 undergoes AARS1-mediated lact","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843183","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}
Linshan Xie, Mengting Sun, Yujie Zheng, Zezhong Yu, Hui Kong, Jinjie Yu, Shaohua Lu, Yong Zhang, Jie Hu, Hongyi Xin, Jian Zhou, Xiangdong Wang, Charles A. Powell, Fred R. Hirsch, Chunxue Bai, Yuanlin Song, Jun Yin, Dawei Yang
<div> <section> <h3> Background</h3> <p>Early tumour vascular invasion contributes to cancer progression. Tip cells, a subset of tumour endothelial cells, significantly decline after anti-angiogenic therapy. However, their behaviour and the roles of their signature genes during early invasion are incompletely understood.</p> </section> <section> <h3> Methods</h3> <p>This study employed single-cell transcriptomic analysis and 10x Genomics Visium spatial transcriptomics on fresh lung tissues from patients with pulmonary nodules and from <i>Kras<sup>G12D</sup></i> (K) and <i>Kras<sup>G12D</sup>Tgfbr2<sup>−/−</sup></i> (KT) mice. The role of plasma vesicle-associated protein (PLVAP), a tip cell marker, was further examined using survival databases, immunofluorescence, in vitro co-culture, cell migration, invasion assays and endothelial tube formation.</p> </section> <section> <h3> Results</h3> <p>Tip cell proportions were elevated in early-stage lung adenocarcinoma (LUAD) tissues and KT mice, with evidence suggesting they arise from capillaries type I. PLVAP expression was enriched in tumour endothelial cells, induced by TGFβ1, and negatively correlated with patient prognosis. Functionally, PLVAP promoted endothelial cell invasion, migration and angiogenesis, and regulated tumour cell invasiveness. Intercellular analysis revealed that some tip cells also expressed TGFβ1, which may act on adjacent tumour cells to enhance invasion during early tumour development.</p> </section> <section> <h3> Conclusion</h3> <p>Tip cells increased during early LUAD progression and likely evolved from capillaries type I. Their marker PLVAP was associated with poor prognosis and pro-invasive endothelial behaviour. Tumour-secreted TGFβ1 upregulated PLVAP in endothelial cells, promoting angiogenesis and tumour invasion. Additionally, tip-cell-derived TGFβ1 may further stimulate tumour aggressiveness, highlighting a reciprocal interaction that contributes to early tumour progression.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Tip cells expand during early LUAD progression and likely originate from capillary type I endothelial cells.</li> <li>Tumour-derived TGFβ1 induces PLVAP expression in endothelial cells, linking tumour signals to vascular activation.</li> <li>PLVAP enhances endothelial cell migration, invasion
{"title":"PLVAP mediates the regulation of the tumour microenvironment in early-stage lung adenocarcinoma","authors":"Linshan Xie, Mengting Sun, Yujie Zheng, Zezhong Yu, Hui Kong, Jinjie Yu, Shaohua Lu, Yong Zhang, Jie Hu, Hongyi Xin, Jian Zhou, Xiangdong Wang, Charles A. Powell, Fred R. Hirsch, Chunxue Bai, Yuanlin Song, Jun Yin, Dawei Yang","doi":"10.1002/ctm2.70532","DOIUrl":"10.1002/ctm2.70532","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Early tumour vascular invasion contributes to cancer progression. Tip cells, a subset of tumour endothelial cells, significantly decline after anti-angiogenic therapy. However, their behaviour and the roles of their signature genes during early invasion are incompletely understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study employed single-cell transcriptomic analysis and 10x Genomics Visium spatial transcriptomics on fresh lung tissues from patients with pulmonary nodules and from <i>Kras<sup>G12D</sup></i> (K) and <i>Kras<sup>G12D</sup>Tgfbr2<sup>−/−</sup></i> (KT) mice. The role of plasma vesicle-associated protein (PLVAP), a tip cell marker, was further examined using survival databases, immunofluorescence, in vitro co-culture, cell migration, invasion assays and endothelial tube formation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Tip cell proportions were elevated in early-stage lung adenocarcinoma (LUAD) tissues and KT mice, with evidence suggesting they arise from capillaries type I. PLVAP expression was enriched in tumour endothelial cells, induced by TGFβ1, and negatively correlated with patient prognosis. Functionally, PLVAP promoted endothelial cell invasion, migration and angiogenesis, and regulated tumour cell invasiveness. Intercellular analysis revealed that some tip cells also expressed TGFβ1, which may act on adjacent tumour cells to enhance invasion during early tumour development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Tip cells increased during early LUAD progression and likely evolved from capillaries type I. Their marker PLVAP was associated with poor prognosis and pro-invasive endothelial behaviour. Tumour-secreted TGFβ1 upregulated PLVAP in endothelial cells, promoting angiogenesis and tumour invasion. Additionally, tip-cell-derived TGFβ1 may further stimulate tumour aggressiveness, highlighting a reciprocal interaction that contributes to early tumour progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Tip cells expand during early LUAD progression and likely originate from capillary type I endothelial cells.</li>\u0000 \u0000 <li>Tumour-derived TGFβ1 induces PLVAP expression in endothelial cells, linking tumour signals to vascular activation.</li>\u0000 \u0000 <li>PLVAP enhances endothelial cell migration, invasion","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809631","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}
<p>Current vaccine platforms vary in their intrinsic strengths and limitations, making their suitability dependent on pathogen-specific features and the epidemiological setting. In the early phase of an outbreak, the ability to rapidly design, manufacture and implement a vaccine is essential. However, as the epidemic progresses – or when addressing endemic pathogens – the relative priorities may shift towards durability of protection, booster compatibility, manufacturability at global scale and affordability. Currently, no vaccine platform meets all these requirements, highlighting the need for continued innovation.</p><p>During the COVID-19 pandemic, messenger RNA (mRNA) vaccines proved their potential by enabling an exceptionally rapid vaccine rollout.<span><sup>1</sup></span> However, although these vaccines demonstrated high initial immunogenicity, the vaccine-induced neutralizing antibody titres declined rapidly, making repeated booster immunizations necessary to maintain protection.<span><sup>2</sup></span> Unfortunately, evidence suggest that the short antibody durability reflects an intrinsic property of the mRNA platform rather than an antigen-specific phenomenon.<span><sup>3</sup></span></p><p>In contrast, a single dose of a human papillomavirus capsid virus-like particle (cVLP) vaccine can provide long-lasting protection by inducing durable antibody responses.<span><sup>4</sup></span> This capacity for sustained humoral immunity is unique among subunit vaccines and is attributed to the dense, ordered, and repetitive epitope display characteristic of cVLPs, which efficiently drives robust germinal-centre reactions and long-lived plasma cell formation.<span><sup>5</sup></span></p><p>Supporting this concept, we previously developed a modular Tag/Catcher protein-based cVLP system that enabled the production of a non-adjuvanted COVID-19 vaccine which in a phase III clinical trial demonstrated non-inferiority to the licensed mRNA vaccine Comirnaty (NCT05329220). However, cVLP vaccines have similar manufacturing timelines as other protein-based vaccines, making frequent antigen updates to keep pace with emerging viral variants challenging.</p><p>Therefore, to combine the immunological properties of cVLPs with the manufacturing advantages of genetic vaccines, we developed a modular platform, in which co-delivery of gene sequences encoding the target antigen and a self-assembling cVLP enables in vivo formation of cVLP displaying the antigen at high density (Figure 1). Using the clinical-stage malaria transmission-blocking Pfs25 antigen as our model, we could demonstrate that this strategy enhances both humoral and cellular immunity, providing a dose sparing potential.</p><p>The platform is based on a genetically launched (mRNA or DNA) system encoding two components: a cVLP scaffold and a target antigen. Each component is genetically fused to a complementary split-protein (Tag or Catcher) binding partner, enabling spontaneous formation of covale
目前的疫苗平台在其内在优势和局限性方面各不相同，使其适用性取决于病原体特异性特征和流行病学环境。在疫情的早期阶段，快速设计、制造和实施疫苗的能力至关重要。然而，随着流行病的发展，或者在处理地方性病原体时，相对的优先事项可能会转向保护的持久性、增强剂的兼容性、在全球范围内的可制造性和可负担性。目前，没有任何疫苗平台能够满足所有这些要求，这突出了继续创新的必要性。在2019冠状病毒病大流行期间，信使RNA （mRNA）疫苗通过实现异常快速的疫苗推广，证明了其潜力然而，尽管这些疫苗显示出较高的初始免疫原性，但疫苗诱导的中和抗体滴度迅速下降，因此需要重复加强免疫以保持保护作用不幸的是，有证据表明，短抗体耐久性反映了mRNA平台的内在特性，而不是抗原特异性现象。相比之下，单剂量的人乳头瘤病毒衣壳病毒样颗粒（cVLP）疫苗可以通过诱导持久的抗体反应提供持久的保护这种持续体液免疫的能力在亚单位疫苗中是独一无二的，这归因于cVLPs密集、有序和重复的表位显示特征，这有效地驱动了强大的生发中心反应和长寿命的浆细胞形成。为了支持这一概念，我们之前开发了一种模块化的基于Tag/Catcher蛋白的cvpp系统，该系统能够生产一种无佐剂的COVID-19疫苗，该疫苗在III期临床试验中证明其不优于已获许可的mRNA疫苗Comirnaty （NCT05329220）。然而，cVLP疫苗与其他基于蛋白质的疫苗具有相似的生产时间表，这使得频繁的抗原更新以跟上新出现的病毒变体具有挑战性。因此，为了将cVLP的免疫学特性与基因疫苗的制造优势结合起来，我们开发了一个模块化平台，在该平台中，编码目标抗原的基因序列与自组装的cVLP共同递送，可以在体内形成高密度显示抗原的cVLP（图1）。使用临床阶段疟疾传播阻断Pfs25抗原作为我们的模型，我们可以证明这种策略增强了体液和细胞免疫，提供了剂量节约的潜力。该平台基于基因启动（mRNA或DNA）系统，编码两个组件：cVLP支架和靶抗原。每个成分在基因上融合到一个互补的分裂蛋白（标签或捕集器）结合伙伴，使cvpp和抗原之间自发形成共价键接种疫苗后，宿主细胞将这两种成分表达并组装成抗原修饰的cVLPs，最终分泌到细胞外空间。通过利用Tag/Catcher偶联系统，该方法提供了一个模块化的平台，使cVLP支架和抗原的不同组合能够混合和匹配，从而消除了为每个新靶标重新设计融合结构的需要。第一代mRNA疫苗通常以单体或最小多聚体形式表达抗原。然而，该系统能够以高度有序、重复和颗粒形式递送抗原，从而增强免疫反应的强度和潜在的持久性。Cyrielle Fougeroux和Adam F. Sander是一项专利申请的共同发明人，该专利申请涉及基于核酸的模块化cVLP疫苗平台（P5856PC00）的交付，并且是AdaptVac的股东，该公司开发并商业化VLP显示技术。
{"title":"A modular vaccine platform merging the rapid development of genetic vaccines with the immunogenicity of virus-like particles","authors":"Adam F. Sander, Cyrielle Fougeroux","doi":"10.1002/ctm2.70560","DOIUrl":"10.1002/ctm2.70560","url":null,"abstract":"<p>Current vaccine platforms vary in their intrinsic strengths and limitations, making their suitability dependent on pathogen-specific features and the epidemiological setting. In the early phase of an outbreak, the ability to rapidly design, manufacture and implement a vaccine is essential. However, as the epidemic progresses – or when addressing endemic pathogens – the relative priorities may shift towards durability of protection, booster compatibility, manufacturability at global scale and affordability. Currently, no vaccine platform meets all these requirements, highlighting the need for continued innovation.</p><p>During the COVID-19 pandemic, messenger RNA (mRNA) vaccines proved their potential by enabling an exceptionally rapid vaccine rollout.<span><sup>1</sup></span> However, although these vaccines demonstrated high initial immunogenicity, the vaccine-induced neutralizing antibody titres declined rapidly, making repeated booster immunizations necessary to maintain protection.<span><sup>2</sup></span> Unfortunately, evidence suggest that the short antibody durability reflects an intrinsic property of the mRNA platform rather than an antigen-specific phenomenon.<span><sup>3</sup></span></p><p>In contrast, a single dose of a human papillomavirus capsid virus-like particle (cVLP) vaccine can provide long-lasting protection by inducing durable antibody responses.<span><sup>4</sup></span> This capacity for sustained humoral immunity is unique among subunit vaccines and is attributed to the dense, ordered, and repetitive epitope display characteristic of cVLPs, which efficiently drives robust germinal-centre reactions and long-lived plasma cell formation.<span><sup>5</sup></span></p><p>Supporting this concept, we previously developed a modular Tag/Catcher protein-based cVLP system that enabled the production of a non-adjuvanted COVID-19 vaccine which in a phase III clinical trial demonstrated non-inferiority to the licensed mRNA vaccine Comirnaty (NCT05329220). However, cVLP vaccines have similar manufacturing timelines as other protein-based vaccines, making frequent antigen updates to keep pace with emerging viral variants challenging.</p><p>Therefore, to combine the immunological properties of cVLPs with the manufacturing advantages of genetic vaccines, we developed a modular platform, in which co-delivery of gene sequences encoding the target antigen and a self-assembling cVLP enables in vivo formation of cVLP displaying the antigen at high density (Figure 1). Using the clinical-stage malaria transmission-blocking Pfs25 antigen as our model, we could demonstrate that this strategy enhances both humoral and cellular immunity, providing a dose sparing potential.</p><p>The platform is based on a genetically launched (mRNA or DNA) system encoding two components: a cVLP scaffold and a target antigen. Each component is genetically fused to a complementary split-protein (Tag or Catcher) binding partner, enabling spontaneous formation of covale","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809603","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}
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