Signal Transduction and Targeted Therapy最新文献

{"title":"Meplazumab, a CD147 antibody, for severe COVID-19: a double-blind, randomized, placebo-controlled, phase 3 clinical trial","authors":"Huijie Bian, Liang Chen, Zheng Zhang, Ai-Dong Wen, Zhao-Hui Zheng, Li-Qiang Song, Meng-Ying Yao, Ying-Xia Liu, Xi-Jing Zhang, Hong-Lin Dong, Jian-Qi Lian, Lei Pan, Yu Liu, Xing Gu, Hui Zhao, Jing-Wen Wang, Qing-Yi Wang, Kui Zhang, Jun-Feng Jia, Rong-Hua Xie, Xing Luo, Xiang-Hui Fu, Yan-Yan Jia, Jun-Na Hou, Qiu-Yue Tan, Xiao-Xia Chen, Liu-Qing Yang, Yuan-Long Lin, Xiao-Xia Wang, Lei Zhang, Qin-Jing Zeng, Wen-Jie Li, Rui-Xuan Wang, Yang Zhang, Xiu-Xuan Sun, Bin Wang, Xu Yang, Jian-Li Jiang, Ling Li, Jiao Wu, Xiang-Min Yang, Hai Zhang, Ying Shi, Xiao-Chun Chen, Hao Tang, Hong-Wei Shi, Shuang-Shuang Liu, Yong Yang, Tian-Yi Yang, Ding Wei, Zhi-Nan Chen, Ping Zhu","doi":"10.1038/s41392-025-02208-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02208-9","url":null,"abstract":"<p>Meplazumab, a humanized CD147 antibody, showed favorable safety and clinical benefits in phase 1 and phase 2/3 seamless clinical studies. Further evaluation of its therapeutic efficacy in patients with severe COVID-19 is needed. In this phase 3 add-on study, we randomized patients with severe COVID-19 in a 1:1 ratio to receive 0.2 mg/kg meplazumab or placebo via intravenous injection, and evaluated efficacy and safety within 56 days. Between February 2023 and November 2023, 108 patients with severe COVID-19 were randomized to two groups, with their baseline characteristics generally balanced. The primary endpoint, 28-day all-cause mortality was 1.96% in the meplazumab group vs 7.69% in the placebo group (<i>P</i> = 0.1703). Supplementary analysis using composite strategy indicated a significant reduction of 28-day all-cause mortality in meplazumab compared to placebo (3.92% vs 15.38%, <i>P</i> = 0.044). Meplazumab also significantly reduced the mortality in smoking subjects on day 28 (<i>P</i> = 0.047) compared to placebo in supplementary analysis. The secondary endpoint, 56-day all-cause mortality, was 1.96% in the meplazumab group and 11.54% in the placebo group (<i>P</i> = 0.048), which was 3.92% and 15.38%, respectively (<i>P</i> = 0.044) by supplementary analysis. Additional secondary endpoints showed potential benefits, including increased hospital discharge rates, improved clinical outcomes, and improved viral nucleotide conversion rate. Meplazumab demonstrated good safety and tolerability, with no grade ≥ 3 TEAEs observed. These promising results indicate that meplazumab reduces mortality and enhances clinical benefits in severe COVID-19 patients with a good safety profile, providing effective and specific therapeutics for severe COVID-19 (the trial was registered at ClinicalTrials.gov (NCT05679479)).</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"6 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic gene fusions in cancer: from biology to therapy","authors":"Stephen V. Liu, Misako Nagasaka, Judith Atz, Flavio Solca, Leonhard Müllauer","doi":"10.1038/s41392-025-02161-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02161-7","url":null,"abstract":"<p>Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types. Cancers driven by gene fusion products tend to respond well to targeted therapies, where available; thus, detection of potentially targetable oncogenic fusions is necessary to select optimal treatment. Detection methods include non-sequencing methods, such as fluorescence in situ hybridization and immunohistochemistry, and sequencing methods, such as DNA- and RNA-based next-generation sequencing (NGS). While NGS is an efficient way to analyze multiple genes of interest at once, economic and technical factors may preclude its use in routine care globally, despite several guideline recommendations. The aim of this review is to present a summary of oncogenic gene fusions, with a focus on fusions that affect tyrosine kinase signaling, and to highlight the importance of testing for oncogenic fusions. We present an overview of the identification of oncogenic gene fusions and therapies approved for the treatment of cancers harboring gene fusions, and summarize data regarding treating fusion-positive cancers with no current targeted therapies and clinical studies of fusion-positive cancers. Although treatment options may be limited for patients with rare alterations, healthcare professionals should identify patients most likely to benefit from oncogenic gene fusion testing and initiate the appropriate targeted therapy to achieve optimal treatment outcomes.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"119 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Overexpression of CIP2A is associated with poor prognosis in multiple myeloma","authors":"Xuewen Liu, Wei Cao, Shanshan Qin, Te Zhang, Junnian Zheng, Ying Dong, Pinghong Ming, Qian Cheng, Zheng Lu, Yang Guo, Baofu Zhang, Ying Liu","doi":"10.1038/s41392-025-02225-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02225-8","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/sigtrans.2017.13, published online 26 May 2017</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"112 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel derivatives of brincidofovir and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine inhibit orthopoxviruses and human adenoviruses more potently than brincidofovir","authors":"Yifan Zhang, Yanmin Wan, Cuiyuan Guo, Zhaoqin Zhu, Chao Qiu, Jiasheng Lu, Yanan Zhou, Jiaojiao Zheng, Fahui Dai, Xiaoyang Cheng, Kunlu Deng, Wanhai Wang, Youchun Wang, Wenhong Zhang","doi":"10.1038/s41392-025-02207-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02207-w","url":null,"abstract":"<p>Brincidofovir (BCV) and tecovirimat are the only two chemical drugs that have been approved to treat smallpox and can be requested for monkeypox (Mpox) treatment through a single-patient Emergency Investigational New Drug (EIND) application. Disappointedly, the efficacy of tecovirimat manifested in recent clinical trials is far from being satisfactory, while the clinical efficacy of BCV is still inconclusive. Given that monkeypox virus (MPXV), variola and other emerging orthopoxviruses are posing serious threats to global health, it is urgent to develop better therapeutics. In this study, we tested the antiviral effects of three novel prodrugs, which were designed based on previously reported parent drugs, either (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMPC, cidofovir) or (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA). We found that one of the (S)-HPMPA-based prodrugs, ODE-(S)-HPMPA formate, exhibited significantly better anti-orthopoxvirus activity than BCV both in vitro and in vivo, which also inhibited human adenovirus type 2 and type 21 more efficiently than BCV. Most strikingly, the EC₅₀ and EC₉₀ of ODE-(S)-HPMPA formate against MPXV were more than 40-fold lower than those of BCV. In contrast, we observed that the anti-herpes simplex virus type 1 (HSV-1) activities of the (S)-HPMPA-based prodrugs were less effective than those of the cidofovir-based prodrugs (BCV and BCV formate), especially in vivo. Moreover, we showed for the first time that cytidine and adenine analog combined therapies could provide mice with complete protection against lethal challenges of both vaccinia and HSV-1. Collectively, we propose that both the ODE-(S)-HPMPA formate and the BCV/ODE-(S)-HPMPA formate combination are worth further investigations for their potential clinical applications.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"65 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adiponectin to the rescue: extracorporeal photopheresis for managing immune checkpoint inhibitor-induced toxicities","authors":"Robin Reschke, Alexander H. Enk, Jessica C. Hassel","doi":"10.1038/s41392-025-02205-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02205-y","url":null,"abstract":"<p>In a recent study published in <i>Cancer Cell</i>, Braun et al. introduced extracorporeal photopheresis (ECP) as a novel immunomodulatory approach to mitigate immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) without compromising anti-tumor immunity.¹ ECP suppressed Th1/Trm cell activation and neutrophil infiltration while enhancing an anti-inflammatory macrophage phenotype through adiponectin, facilitating the resolution of steroid-refractory irAEs.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"3 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Personalized cancer vaccination is emerging: lessons learnt from renal cancer and challenges for broader application","authors":"Elke Schaeffeler, Juliane Walz, Matthias Schwab","doi":"10.1038/s41392-025-02204-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02204-z","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"4 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease","authors":"Chandana Thimme Gowda, Mallikarjuna Siraganahalli Eshwaraiah, Jiaohong Wang, Youngyi Lim, Maria Lauda Tomasi, Nirmala Mavila, Komal Ramani","doi":"10.1038/s41392-025-02202-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02202-1","url":null,"abstract":"<p>Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). The goal of this work is to examine how AKAP12’s PKA-anchoring ability regulates outcomes of alcohol-associated steatosis. Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12. Alcohol exposure diminished AKAP12’s interaction with PKA regulatory subunits and PKA substrates, acetyl CoA carboxylase (ACC1), pyruvate dehydrogenase (PDHA) and adipose triglyceride lipase (ATGL). Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes. Forced expression of <i>AKAP12</i> restored alcohol suppressed PKA activation and inhibited lipid accumulation, whereas silencing had the reverse effect. Since <i>AKAP12</i> sustained PKA activity, we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis. Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12’s PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity, enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation, increased lipid accumulation and reduced FAO in hepatocytes. Overexpression of <i>AKAP12</i> in mouse livers sustained PKA activation, diminished basal and alcohol potentiated triglyceride content, and regulated inflammatory signaling altered by alcohol. Mechanistically, we discovered that alcohol enhanced the inhibitory activity of a kinase, serine/threonine-protein kinase 25 (STK25) on PKA that regulated its interaction with AKAP12. In conclusion, the AKAP12-PKA scaffold controls lipogenic signaling, disruption of which favors steatosis during ALD.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tripeptide DT-109 (Gly-Gly-Leu) attenuates atherosclerosis and vascular calcification in nonhuman primates","authors":"Linying Jia, Pengxiang Qu, Yang Zhao, Liang Bai, Honghao Ren, Ao Cheng, Zeyao Ma, Cheng Ding, Yongjie Deng, Lingxuan Kong, Ying Zhao, Oren Rom, Yajie Chen, Naqash Alam, Wenbin Cao, Sixue Zhai, Zuowen Zheng, Zhi Hu, Lu Wang, Yabing Chen, Sihai Zhao, Jifeng Zhang, Jianglin Fan, Y. Eugene Chen, Enqi Liu","doi":"10.1038/s41392-025-02201-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02201-2","url":null,"abstract":"<p>Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events. However, effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking. This study investigated the efficacy of DT-109 (Gly-Gly-Leu) in attenuating atherosclerosis and calcification in nonhuman primates, exploring its broader therapeutic potential. In this study, twenty male cynomolgus monkeys were administered a cholesterol-rich diet <i>ad libitum</i> for 10 months. Then, the animals were treated either orally with DT-109 (150 mg/kg/day) or a vehicle (H₂O) for 5 months while continuing on the same diet. Plasma lipid levels were measured monthly and at the end of the experiment, pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed. To explore possible molecular mechanisms, the effects of DT-109 on smooth muscle cells (SMCs) were examined in vitro. We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries. Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification. RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors <i>NLRP3</i>, <i>AIM2</i>, and <i>CASP1</i>, the oxidative stress factors <i>NCF2</i> and <i>NCF4</i>, and the osteogenic factors <i>RUNX2</i>, <i>COL1A1</i>, <i>MMP2</i>, and <i>MMP9</i>, while simultaneously upregulating the expression of the SMCs contraction markers <i>ACTA2</i>, <i>CNN1</i>, and <i>TAGLN</i>. Furthermore, DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro. These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification. These findings, in conjunction with insights from our previous studies, position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"89 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From CRISPR screens to circuits: identifying key regulators in T cell activation and state transitions","authors":"Maria Silvia Roman Azcona, Toni Cathomen, Claudio Mussolino","doi":"10.1038/s41392-025-02200-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02200-3","url":null,"abstract":"<p>A recent study published in <i>Nature</i> by Maya M. Arce and colleagues unveils the role of central gene circuits in governing the delicate balance between T cell rest and T cell activation.¹ This work bridges fundamental molecular biology with findings in preclinical models, providing insights into context-specific gene regulation and potential therapeutic targets for immune modulation.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"172 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances","authors":"Chen Xue, Qingfei Chu, Qingmiao Shi, Yifan Zeng, Juan Lu, Lanjuan Li","doi":"10.1038/s41392-025-02142-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02142-w","url":null,"abstract":"<p>The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling’s involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"108 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}