Signal Transduction and Targeted Therapy最新文献

{"title":"Dopamine as a teaching signal: understanding its role in shaping individual behavior","authors":"Seung Chan Kim, Sehwan Kim, Sang Ryong Kim","doi":"10.1038/s41392-025-02406-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02406-5","url":null,"abstract":"<p>In a recent publication in <i>Cell</i>, Liebana and colleagues demonstrate that dopamine acts as a circuit-specific teaching signal, shaping individual learning trajectories over time. These reward prediction error (RPE) signals refine behavior by selectively reinforcing neural pathways, revealing a key mechanism through which dopamine guides personalized learning strategies beyond classical reward-based models.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"30 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995490","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":"Understanding the toxicity induced by radiation-triggered neuroinflammation and the on-demand design of targeted peptide nanodrugs.","authors":"Yue Shang,Xueyin Hu,Meixia Ren,Longbo Ma,Xiaoyu Zhao,Cong Gao,Lumeng Zhang,Shuqin Li,Luntao Liu,Bingwen Zou,Saijun Fan","doi":"10.1038/s41392-025-02375-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02375-9","url":null,"abstract":"Radiation-induced brain injury (RIBI) represents a severe complication of cranial radiotherapy, substantially diminishing patients' quality of life. Unlike conventional brain injuries, RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes. Despite significant progress in understanding the molecular mechanisms related to neuroinflammation, the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear. Additionally, targeted neuroprotective strategies for RIBI are currently lacking. In this study, we systematically characterized the pathophysiology of RIBI using zebrafish (larvae/adults) and murine models. We established direct associations between neuronal damage and cognitive-behavioral deficits. Mechanistically, we proposed a ROS-mitochondrial-immune axis. Specifically, radiation-induced ROS lead to mitochondrial dysfunction, resulting in the leakage of mitochondrial DNA into the cytosol. This, in turn, activated the cGAS-STING pathway, thereby driving persistent microglia-mediated neuroinflammation. Furthermore, we engineered a dual-function nanotherapeutic agent, Pep-Cu5.4O@H151. This agent integrates ultrasmall copper-based nanozymes (Cu5.4O) for ROS scavenging and H151 (a STING inhibitor) and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia. This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades. Our research provided an in-depth analysis of radiation-induced neurotoxicity, clarifying the crucial ROS-mitochondrial-immune axis. Moreover, we have developed a precise therapeutic strategy on the basis of this mechanism.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"62 1","pages":"286"},"PeriodicalIF":39.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962669","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":"UGCG and the glycosphingolipid rheostat: a metabolic checkpoint governing immune activation and tumor immune evasion","authors":"Sumei Chen, Xiang Wang, Youssef Jounaidi","doi":"10.1038/s41392-025-02413-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02413-6","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"66 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930595","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":"Pancancer outcome prediction via a unified weakly supervised deep learning model","authors":"Wei Yuan, Yijiang Chen, Biyue Zhu, Sen Yang, Jiayu Zhang, Ning Mao, Jinxi Xiang, Yuchen Li, Yuanfeng Ji, Xiangde Luo, Kangning Zhang, Xiaohan Xing, Shuo Kang, Dongyuan Xiao, Fang Wang, Jinkun Wu, Haiyan Zhang, Hongping Tang, Himanshu Maurya, German Corredor, Cristian Barrera, Yufei Zhou, Krunal Pandav, Junhan Zhao, Prantesh Jain, Luke Delasos, Junzhou Huang, Kailin Yang, Theodoros N. Teknos, James Lewis, Shlomo Koyfman, Nathan A. Pennell, Kun-Hsing Yu, Xiao Han, Jing Zhang, Xiyue Wang, Anant Madabhushi","doi":"10.1038/s41392-025-02374-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02374-w","url":null,"abstract":"<p>Accurate prognosis prediction is essential for guiding cancer treatment and improving patient outcomes. While recent studies have demonstrated the potential of histopathological images in survival analysis, existing models are typically developed in a cancer-specific manner, lack extensive external validation, and often rely on molecular data that are not routinely available in clinical practice. To address these limitations, we present PROGPATH, a unified model capable of integrating histopathological image features with routinely collected clinical variables to achieve pancancer prognosis prediction. PROGPATH employs a weakly supervised deep learning architecture built upon the foundation model for image encoding. Morphological features are aggregated through an attention-guided multiple instance learning module and fused with clinical information via a cross-attention transformer. A router-based classification strategy further refines the prediction performance. PROGPATH was trained on 7999 whole-slide images (WSIs) from 6,670 patients across 15 cancer types, and extensively validated on 17 external cohorts with a total of 7374 WSIs from 4441 patients, covering 12 cancer types from 8 consortia and institutions across three continents. PROGPATH achieved consistently superior performance compared with state-of-the-art multimodal prognosis prediction models. It demonstrated strong generalizability across cancer types and robustness in stratified subgroups, including early- and advanced-stage patients, treatment cohorts (radiotherapy and pharmaceutical therapy), and biomarker-defined subsets. We further provide model interpretability by identifying pathological patterns critical to PROGPATH’s risk predictions, such as the degree of cell differentiation and extent of necrosis. Together, these results highlight the potential of PROGPATH to support pancancer outcome prediction and inform personalized cancer management strategies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"116 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930596","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: Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness","authors":"Bin He, Rui Gao, Shasha Lv, Ailin Chen, Junxiu Huang, Luoxuan Wang, Yunxiu Feng, Jiesi Feng, Bing Liu, Jie Lei, Bing Deng, Bin He, Bai Cui, Fei Peng, Min Yan, Zifeng Wang, Eric W-F Lam, Bilian Jin, Zhiming Shao, Yulong Li, Jianwei Jiao, Xi Wang, Quentin Liu","doi":"10.1038/s41392-025-02389-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02389-3","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-023-01487-4, published online 19 July 2023</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927919","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":"“Good” fats, bad news: HDL-delivered vitamin E shields tumors from ferroptosis","authors":"Dong Wook Choi, Eun-Woo Lee","doi":"10.1038/s41392-025-02373-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02373-x","url":null,"abstract":"<p>In a recent study published in <i>Nature</i>, Calhoon et al.¹ reported that glycosaminoglycan (GAG)-mediated uptake of lipoproteins protects cancer cells from ferroptosis by delivering α-tocopherol, the most abundant form of vitamin E. This discovery offers potential therapeutic opportunities to either target GAG-dependent lipid uptake or modulate dietary vitamin E to enhance ferroptosis-based cancer therapies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"25 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927920","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":"Arterial stiffness and vascular aging: mechanisms, prevention, and therapy","authors":"Maximilian Jonathan Herzog, Patrick Müller, Katharina Lechner, Marvin Stiebler, Philipp Arndt, Matthias Kunz, Dörte Ahrens, Alexander Schmeißer, Stefanie Schreiber, Ruediger C. Braun-Dullaeus","doi":"10.1038/s41392-025-02346-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02346-0","url":null,"abstract":"<p>Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. The central underlying mechanisms of cardiovascular diseases are vascular aging and associated arterial stiffness. Arterial stiffness is characterized by structural (e.g., tunica media calcification, alterations in vascular smooth muscle cells, and fibrosis) and functional (e.g., loss of <i>Windkessel function</i>, elevated pulse pressure, and development of isolated systolic hypertension) vascular changes that cause microvascular dysfunction and end-organ damage (e.g., heart failure, vascular dementia, hypertensive retinopathy, and chronic kidney disease). Current research indicates that arterial stiffness is an independent risk factor for cardiovascular diseases and represents a potential target for personalized prevention and therapeutic approaches. In this review, we summarize the pathophysiological mechanisms of vascular aging and arterial stiffness, outline the resulting end-organ damage, present different methods for the measurement of arterial stiffness, highlight the potential role of prevention and therapy, and provide future perspectives for arterial stiffness research. The purpose of this review is to provide a state-of-the-art interdisciplinary and translational approach to arterial stiffness, highlighting unique pathophysiological mechanisms (e.g., perivascular adipose tissue, extracellular vesicles), clinical relevance, and future directions.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"59 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923911","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":"Bicarbonate-integrated transarterial chemoembolization (TACE) in real-world hepatocellular carcinoma","authors":"Kai Jin, Siying Zeng, Bin Li, Guangqiang Zhang, Jianjun Wu, Xun Hu, Ming Chao","doi":"10.1038/s41392-025-02400-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02400-x","url":null,"abstract":"<p>The objective response rate of conventional transarterial chemoembolization (TACE) for locoregional control of hepatocellular carcinoma (HCC) is approximately 50%. We previously developed bicarbonate-integrated TACE, termed TILA-TACE, which demonstrated 100% effectiveness for locoregional control of unresectable HCC. This study aimed to validate its efficacy, selectivity, and safety in real-world clinical practice (ChiCTR-ONC-17013416). A total of 413 patients were enrolled, including 40 (9.7%) with early-stage HCC, 29 (7.0%) with intermediate-stage HCC, and 344 (83.3%) with advanced-stage HCC. Primary tumors and macrovascular invasion/extrahepatic metastases were treated with TILA-TACE and radiation therapy, respectively. The side effects of TILA-TACE were recorded. The objective response rate of HCC tumors to TILA-TACE was 99.01%, including a complete response in 72.77% of patients. The objective response rate of tumor thrombus to radiation therapy was 96.88%. During a median follow-up of 38 months, there were 1 and 4 deaths among early- and intermediate-stage patients, respectively. The median survival of advanced-stage patients was 27 months. We found that intrahepatic metastases accounted for 70.4% (107/152) of cancer-related deaths after effective control of primary tumors and vascular invasion. The main adverse events associated with TILA-TACE were transient liver enzyme or bilirubin abnormalities (86.44% and 56.66%, respectively), which was consistent with the known side-effect profile of TACE. In conclusion, TILA-TACE is a novel and highly effective treatment for the local control of HCC with a tolerable safety profile. When combined with radiation therapy for macrovascular invasion, it offers significant survival benefits for patients with advanced HCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"106 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923943","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":"Focal adhesion kinase/Src family kinase axis-mediated tyrosine phosphorylation of metabolic enzymes facilitates tumor metastasis","authors":"Jie Chen, Jing Zhang, Yuheng Zhu, Yanmeng Zhu, Jingyuan Pang, Qingnan Wu, Yan Wang, Qimin Zhan","doi":"10.1038/s41392-025-02395-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02395-5","url":null,"abstract":"<p>Lymph node metastasis is crucial for esophageal squamous cell carcinoma (ESCC) malignancy. However, the molecular drivers and related mechanisms of lymph node metastasis in ESCC cells are unclear. In the present study, we found that the tyrosine kinase complex-focal adhesion kinase (FAK)/Src family kinase (SFK) axis specifically contributes to metabolic reprogramming by inducing the phosphorylation of ATP-citrate synthase (ACLY) Tyr542, Tyr652, and fructose-bisphosphate aldolase A (ALDOA) Tyr174, Tyr302, or Tyr328 sites in both primary and metastatic ESCC cells. Mechanistically, activated ACLY and ALDOA and their metabolites drive a transcriptional program in primary tumors that induces cyclin-dependent kinase 7/9 (CDK7/9) complex-mediated expression of DNA replication- and cell proliferation-related molecules. This process functions as an enabler of tumor malignancy. In metastatic tumor cells, metabolic enzymes and their products facilitate the transcriptional activity of Yamanaka factors to induce the activation of downstream plasticity-related molecules, fueling ESCC cell survival within metastatic lymph nodes. FAK/SFK axis-controlled ACLY and ALDOA tyrosine phosphorylation and downstream transcription factors and effectors in primary and metastatic ESCC cells are strongly associated with poor patient outcomes. We discovered a lead compound, quercetagitrin, that inhibits the phosphorylation of ALDOA at Tyr174, 302, and 328. Moreover, it has been shown to have antitumor effects alone or in combination with FAK/SFK inhibitors both in vivo and in vitro. The inhibition of tyrosine kinase-regulated metabolic enzyme activities and related signaling networks may be a potential strategy for the treatment and diagnosis of metastatic ESCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"39 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923937","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: Aberrant Notch-signaling promotes tumor angiogenesis in esophageal squamous-cell carcinoma","authors":"Cainan Li, Pujie Wu, Xiaoting Xie, Xinjie Chen, Liping Chen, Liang Zhu, Zhixuan Xuan, Tianyuan Liu, Wen Tan, Shaosen Zhang, Dongxin Lin, Chen Wu","doi":"10.1038/s41392-025-02403-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02403-8","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-025-02309-5, published online 22 July 2025</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920732","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}