Signal Transduction and Targeted Therapy最新文献

{"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}

{"title":"Chronic mild stress exacerbates atrial fibrillation and neutrophil extracellular traps formation through S100A8/A9 signaling","authors":"Shan Meng, Tao Huang, Zijun Zhou, Liming Yu, Huishan Wang","doi":"10.1038/s41392-025-02199-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02199-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"34 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775635","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: Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity","authors":"Ke-Wu Zeng, Jing-Kang Wang, Li-Chao Wang, Qiang Guo, Ting-Ting Liu, Fu-Jiang Wang, Na Feng, Xiao-Wen Zhang, Li-Xi Liao, Mei-Mei Zhao, Dan Liu, Yong Jiang, Pengfei Tu","doi":"10.1038/s41392-025-02218-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02218-7","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-020-00447-6, published online 19 February 2021</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"216 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775916","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: LSD1 is required for euchromatic origin firing and replication timing","authors":"Yue Wang, Yunchao Huang, Edith Cheng, Xinhua Liu, Yu Zhang, Jianguo Yang, Jordan T. F. Young, Grant W. Brown, Xiaohan Yang, Yongfeng Shang","doi":"10.1038/s41392-025-02203-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02203-0","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-022-00927-x, published online 13 April 2022</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766545","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":"C/EBPβ activation in vascular smooth muscle cells promotes hyperlipidemia-induced phenotypic transition and arterial stiffness","authors":"Jun Ma, Xiangyu Yang, Yanan Li, Xin Zhang, Kai Liu, Yong Peng, Si Wang, Rufeng Shi, Xingwei Huo, Xueting Liu, Xinran Li, Runyu Ye, Zhipeng Zhang, Changqiang Yang, Lu Liu, Dan Gao, Shanshan Jia, Lirong Sun, Xianghao Zuo, Qingtao Meng, Xiaoping Chen","doi":"10.1038/s41392-025-02196-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02196-w","url":null,"abstract":"<p>Arterial stiffness is a critical factor in cardiovascular and cerebrovascular events, yet clinical practice lacks specific therapeutic targets and biomarkers for its assessment. Hyperlipidemia closely correlates with arterial stiffness, and we observed elevated CCAAT/enhancer-binding protein β (C/EBPβ) expression in atherosclerotic mouse arterial walls. As the arterial medial layer predominantly consists of vascular smooth muscle cells (VSMCs), C/EBPβ‘s role in VSMCs under hyperlipidemia remains unclear. Our findings demonstrate that cholesterol-induced phenotypic transition of contractile VSMCs to macrophage-like cells coincides with C/EBPβ upregulation and activation. The activation of C/EBPβ is closely related to cellular assembly and organization, regulating the cytoskeleton via Disheveled-associated activator of morphogenesis 1 (Daam1). Conditional knockout of C/EBPβ in VSMCs of ApoE^−/− mice alleviated hyperlipidemia-induced vascular remodeling and reduced the elevation of aortic pulse wave velocity. Additionally, C/EBPβ-regulated cytokine platelet-derived growth factor-CC (PDGF-CC) is correlated with brachial-ankle pulse wave velocity in humans. These results indicate that the activation of C/EBPβ promotes the transition of VSMCs from a contractile phenotype to a macrophage-like phenotype by regulating morphological changes, and C/EBPβ activation contributes to hyperlipidemia-induced arterial stiffness. PDGF-CC exhibited a significant association with arterial stiffness and may serve as a promising indicator of arterial stiffness in humans. Our study reveals molecular mechanisms behind hyperlipidemia-induced arterial stiffness and provides potential therapeutic targets and biomarkers.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"104 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758074","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":"A donor PD-1+CD8+ TSCM-like regulatory subset mobilized by G-CSF alleviates recipient acute graft-versus-host-disease","authors":"Dan Liu, Xue Wang, Yuheng Han, Jing Wang, Yidan Sun, Yafei Hou, Qian Wu, Cong Zeng, Xuping Ding, Yingjun Chang, Jiong Hu, Xiaojun Huang, Liming Lu","doi":"10.1038/s41392-025-02183-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02183-1","url":null,"abstract":"<p>Donor selection determines the occurrence of acute graft-versus-host-disease (aGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). To optimize the current clinical donor selection criteria and identify putative donor lymphocyte subsets associated with better recipient outcomes, we analyzed the peripheral CD4⁺ and CD8⁺ subsets in 80 granulocyte colony-stimulating factor (G-CSF) mobilized donors and examined the aGVHD incidence of the corresponding 80 haploidentical and identical allo-HSCT recipients. The G-CSF-induced expansion of subsets varied among donors. We discovered a novel PD-1⁺CD8⁺CD45RA⁺CCR7⁺ T lymphocyte subset in suitable donors that was significantly correlated with lower incidence of aGVHD and post-transplant anti-infection. The anti-aGVHD activity of this subset was confirmed in a validation cohort (<i>n</i> = 30). Single-cell RNA sequencing revealed that this T cell subset exhibited transcriptomic features of stem cell-like memory T cell (T_SCM) with both Treg and Teff activities which indicated its dual functions in aGVHD inhibition and graft-versus-leukemia (GVL) effect. Intriguingly, upon G-CSF mobilization, the donor PD-1⁺CD8⁺ T_SCM-like regulatory cells increased the PD-1 expression in a BCL6-dependent manner. Next, we showed that the mouse counterpart of this subset (PD-1⁺CD8⁺CD44⁻CD62L⁺) ameliorated aGVHD, and confirmed the existence of this subset in clinical recipients. In summary, we, for the first time, identified a novel donor peripheral T cell subset suppressing aGVHD while promoting the immune reconstitution of recipients. It may serve as an indicator for optimal haploidentical and identical donor selection. Importantly, the dual Treg and Teff function of these T cells makes it a promising treatment for not only aGVHD but also auto-immune diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"3 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758078","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: Advances in the structures, mechanisms and targeting of molecular chaperones","authors":"Jinying Gu, Yanyi He, Chenxi He, Qiuyue Zhang, Qifei Huang, Shangjun Bai, Ruoning Wang, Qidong You, Lei Wang","doi":"10.1038/s41392-025-02215-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02215-w","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-025-02166-2, published online 12 March 2025</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758144","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":"Phototherapy in cancer treatment: strategies and challenges","authors":"Yeyu Cai, Tian Chai, William Nguyen, Jiayi Liu, Enhua Xiao, Xin Ran, Yuping Ran, Dan Du, Wei Chen, Xiangyu Chen","doi":"10.1038/s41392-025-02140-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02140-y","url":null,"abstract":"<p>Phototherapy has emerged as a promising modality in cancer treatment, garnering considerable attention for its minimal side effects, exceptional spatial selectivity, and optimal preservation of normal tissue function. This innovative approach primarily encompasses three distinct paradigms: Photodynamic Therapy (PDT), Photothermal Therapy (PTT), and Photoimmunotherapy (PIT). Each of these modalities exerts its antitumor effects through unique mechanisms—specifically, the generation of reactive oxygen species (ROS), heat, and immune responses, respectively. However, significant challenges impede the advancement and clinical application of phototherapy. These include inadequate ROS production rates, subpar photothermal conversion efficiency, difficulties in tumor targeting, and unfavorable physicochemical properties inherent to traditional phototherapeutic agents (PTs). Additionally, the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions. To address these limitations, ongoing research is fervently exploring innovative solutions. The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches’ effectiveness. Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1α pathway may alleviate tumor hypoxia. Moreover, utilizing self-luminescent materials, near-infrared excitation sources, non-photoactivated sensitizers, and wireless light delivery systems can improve light penetration. Furthermore, integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT. This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges—ultimately illuminating pathways for future research aimed at amplifying this intervention’s therapeutic efficacy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758079","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}