Signal Transduction and Targeted Therapy最新文献

{"title":"Bio-barrier-adaptable biomimetic nanomedicines combined with ultrasound for enhanced cancer therapy","authors":"Juan Guo, Xueting Pan, Qingyuan Wu, Ping Li, Chaohui Wang, Shuang Liu, Haoyuan Zhang, Zezhong Huang, Xiaozhou Mou, Huiyu Liu, Jiajia Xue","doi":"10.1038/s41392-025-02217-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02217-8","url":null,"abstract":"<p>Addressing the critical biological barriers of targeted accumulation and deep tumor penetration remains essential for the clinical translation of nanomedicines. However, existing nanomedicines often face challenges during in vivo transportation, including immune clearance, tumor microenvironmental barriers, and limited vascular permeability, which collectively reduce drug delivery efficiency and compromise therapeutic efficacy. Here, we present a bio-barrier-adaptable biomimetic nanoplatform, MSF@CCM, which integrates a mesoporous silica-loaded iron oxyhydroxide (MSF) core camouflaged with a homologous membrane. This design conferred dual functionality: (1) enhanced tumor accumulation and immune evasion by exploiting homologous cell-cell interactions and mimicking “self” markers, thereby effectively bypassing macrophage clearance and surpassing the limitations of traditional targeted drug delivery; and (2) amplified ultrasound (US)-mediated intratumoral penetration. The MSF core, with its unique porous structure and rough surface, significantly enhanced US cavitation effects, transiently disrupting tumor vasculature and facilitating deep penetration of nanomedicines. Upon US triggering, MSF@CCM effectively disrupted intracellular redox homeostasis, potently inducing ferroptosis via lipid peroxidation accumulation, mitochondrial morphological changes, and decreased key protein expression. This combined therapeutic strategy achieved a remarkable 96.5% tumor growth inhibition in vivo while maintaining favorable biocompatibility. Our findings establish a novel paradigm for overcoming multidimensional bio-barriers through biohybrid engineering and physical energy synergy, offering a promising modality for enhanced cancer therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"8 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872165","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":"Tumor immunology: a short IL18 cleavage product promotes cancer immunosurveillance","authors":"Emma Guilbaud, Lorenzo Galluzzi","doi":"10.1038/s41392-025-02213-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02213-y","url":null,"abstract":"<p>In a recent study published in <i>Nature Immunology</i>, Shen et al. have proposed that the caspase 3 (CASP3)-dependent cleavage of interleukin 18 (IL18) in malignant cells exposed to apoptotic inducers generates a short IL18 fragment that operates intracellularly to promote the secretion of IFN-stimulated gene 15 (ISG15) ubiquitin-like modifier, culminating with the recruitment of natural killer (NK) cells to the tumor microenvironment in support of cancer immunosurveillance.¹ While these findings delineate a novel signaling pathway linking atypical proteolytic processing of IL18 by malignant cells to anticancer immunity, the actual implication of CASP3 in such a signal transduction cascade remains unclear.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"19 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862181","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":"Rapavir, a novel inhibitor of sodium taurocholate cotransporting polypeptide, potently blocks hepatitis B virus entry","authors":"Jia He, Haibo Yu, Kunling Song, Ailong Huang, Yongjun Dang, Juan Chen, Zufeng Guo","doi":"10.1038/s41392-025-02214-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02214-x","url":null,"abstract":"<p><b>Dear Editor</b>,</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862194","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":"Glucosidase alpha neutral C promotes influenza virus replication by inhibiting proteosome-dependent degradation of hemagglutinin","authors":"Xinzhong Liao, Qian Xie, Minqi Liang, Qijun Liao, Bi Huang, Shengze Zhang, Feng Zhang, Liangliang Wang, Lifang Yuan, Xuejie Liu, Simin Wen, Chuming Luo, Dayan Wang, Yongkun Chen, Huanle Luo, Yuelong Shu","doi":"10.1038/s41392-025-02227-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02227-6","url":null,"abstract":"<p>The H7N9 influenza virus poses a significant threat to human health, and the mechanism by which it infects humans remains incompletely understood. Our investigation has unveiled significant insights into the role of <i>glucosidase alpha, neutral C</i> (<i>GANC</i>) gene in human H7N9 infections. Through whole genome sequencing (WGS), we identified five low-frequency functional and heterozygous variants of <i>GANC</i> strongly associated with human H7N9 infections compared to healthy controls. Furthermore, we observed a reduction in mRNA and protein expression of GANC following H7N9 virus infection in vitro and in vivo. Subsequent experiments involving GANC demonstrated the promotion of H7N9 virus replication in a stable strain with GANC overexpression. Conversely, GANC knockdown exhibited the ability to restrict influenza A virus (IAV) replication, including H7N9, H9N2, and H1N1, both in vitro and in vivo. This inhibition was mediated by GANC’s ability to promote the degradation of H7N9 hemagglutinin (HA). Moreover, we discovered that GANC knockdown facilitated the degradation of HA in a proteasome-dependent manner. The inhibition caused by GANC knockdown was mediated by promoting direct binding of HA with the proteasome 26S subunit, non-ATPase, 1 (PSMD1) and PSMD2. All five variants in the <i>GANC</i> gene reduced their ability to promote H7N9 virus replication, and also diminished the levels of GANC-induced HA protein expression. Our findings revealed a novel mechanism by which GANC inhibits the proteasome-dependent degradation of HA to promote H7N9 virus replication. These results suggest that GANC may play an important role in IAV replication.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862184","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":"Subnanomolar MAS-related G protein-coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models","authors":"Ghazl Al Hamwi, Mohamad Wessam Alnouri, Sven Verdonck, Piotr Leonczak, Shaswati Chaki, Stefan Frischbutter, Pavel Kolkhir, Michaela Matthey, Constantin Kopp, Marek Bednarski, Yvonne K. Riedel, Daniel Marx, Sophie Clemens, Vigneshwaran Namasivayam, Susanne Gattner, Dominik Thimm, Katharina Sylvester, Katharina Wolf, Andreas E. Kremer, Steven De Jonghe, Daniela Wenzel, Magdalena Kotańska, Hydar Ali, Piet Herdewijn, Christa E. Müller","doi":"10.1038/s41392-025-02209-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02209-8","url":null,"abstract":"<p>The MAS-related G protein-coupled receptor-X2 (MRGPRX2), an orphan receptor expressed on mast cells (MCs), is upregulated upon inflammation and induces hypersensitivity and inflammatory diseases. In contrast to the large number of MRGPRX2 agonists, only a few antagonists have been described, and no optimization has been reported to improve potency, selectivity, and drug-like properties. Antagonists with ancillary inhibition of the putative mouse ortholog MRGPRB2 have not been described. Here, we present a multi-disciplinary approach involving chemistry, biology, and computational science, resulting in the development of a small-molecule MRGPRX2 antagonist (PSB-172656, 3-ethyl-7,8-difluoro-2-isopropylbenzo[4,5]imidazo [1,2-<i>a</i>] pyrimidin-4(1<i>H</i>)-one) based on a fragment screening hit. The compound exhibits metabolic stability, low cytotoxicity, and competitive blockade of MRGPRX2 activation induced by a diverse range of agonists. It displays subnanomolar potency in Ca²⁺ mobilization assays (<i>K</i>_i value 0.142 nM) and was found to block MRGPRX2-mediated Gα_q and Gα_i1 dissociation, in addition to <i>β</i>-arrestin-2 recruitment. PSB-172656 is selective for MRGPRX2 versus all other MRGPRX subtypes. Its effect on MCs was confirmed in cell lines, including rat basophilic leukemia cells (RBL-2H3) recombinantly expressing human MRGPRX2, human Laboratory of Allergic Diseases 2 (LAD2) MCs, and native human skin MCs. PSB-172656 was found to additionally block the putative mouse ortholog of MRGPRX2, MRGPRB2, as determined in Ca²⁺ mobilization assays (<i>K</i>_i 0.302 nM), and to prevent mouse tracheal contractions, local allergic reactions, and systemic anaphylactic symptoms. PSB-172656 constitutes a unique pharmacological tool and has the potential to be developed as a drug for mast cell-mediated hypersensitivity reactions and chronic inflammatory diseases, addressing a huge unmet medical need.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853101","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":"IL-27: overclocking cytotoxic T lymphocytes to boost cancer immunotherapy","authors":"Silvia Dusi, Vincenzo Bronte, Francesco De Sanctis","doi":"10.1038/s41392-025-02212-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02212-z","url":null,"abstract":"<p>In a recent study published in <i>Nature</i>, Breart et al.¹ untangled the controversy surrounding interleukin (IL)-27’s role in regulating T cell differentiation and immune responses in cancer. Their findings reveal that IL-27 enhances the persistence and effector functions of tumor-infiltrating CD8⁺ T lymphocytes (TILs), preventing exhaustion, sustaining T cell-dependent tumor control and immunotherapy efficacy without significant systemic side effects.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"255 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853097","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":"Conversion of Ku80 K568 crotonylation to SUMOylation facilitates DNA non-homologous end joining and cancer radioresistance","authors":"Hongling Zhao, Shanshan Gao, Yang Han, Dafei Xie, Lihui Xuan, Xin Huang, Jinhua Luo, Qian Ran, Gang Li, Hejiang Guo, Weixiang Hu, Jin Jia, Xiaochang Liu, Yuhao Liu, Jinpeng Tan, Chenjun Bai, Yongqing Gu, Teng Ma, Zhongjun Li, Hua Guan, Ruixue Huang, Ping-Kun Zhou","doi":"10.1038/s41392-025-02210-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02210-1","url":null,"abstract":"<p>Chemo-/radioresistance of malignant tumors hampers cancer control and increases patient mortality. Efficient repair of damaged DNA is critical for the maintenance of genomic integrity and fidelity of genetic information. In reverse, increased DNA repair capability in cancer cells contributes to chemo-/radioresistance of malignant tumors. DNA double-strand break (DSB) is the most serious DNA damage and is also the principal molecular basis of radiotherapy. Upon DNA damage, the Ku80 is recruited and forms a critical DNA-PK complex at the DSB sites with Ku70 and the catalytic subunit (DNA-PKcs) to initiate DNA repair. How DNA-PK is assembled and activated is not fully understood. Based on the identification of radiation-reduced Ku80 K568 crotonylation through quantitative global lysine crotonylome analysis, we reveal that Ku80 K568 is crotonylated by p300-CBP-associated factor (PCAF). Upon DNA damage, the K568cr is decrotonylated by HDAC8 (Histone deacetylase 8). Decrotonylation of K568cr empties this site for the subsequent SUMOylation of Ku80 by CBX4. The conversion of Ku80 from K568 crotonylation to SUMOylation facilitates the assembly of DNA-PK complex and autophosphorylation of DNA-PKcs S2056, consequently activating the DSB repair. Moreover, mutation disrupting the post-translational modification (PTM) of Ku80 K568 site sensitizes cancer cells to radiotherapy in tumor-bearing nude mice models. This study elucidates the conversion model between two different forms of PTMs in the regulation of DNA-PK complex assembly and DSB repair, highlighting this model’s potential in controlling chemo-/radioresistance of malignant tumors, as well as expands the atlas of therapeutic targets.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"45 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853096","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":"RNase1-driven ALK-activation is an oncogenic driver and therapeutic target in non-small cell lung cancer","authors":"Zhengyu Zha, Chunxiao Liu, Meisi Yan, Cong Chen, Cheng Yu, Yaohui Chen, Chenhao Zhou, Lu Li, Yi-Chuan Li, Hiro Yamaguchi, Leiguang Ye, Tong Liu, Ying-Nai Wang, Heng-Huan Lee, Wen-Hao Yang, Li-Chuan Chan, Baozhen Ke, Jennifer L. Hsu, Lieming Ding, Dong Ji, Peng Pan, Yiran Meng, Yue Pu, Lunxu Liu, Mien-Chie Hung","doi":"10.1038/s41392-025-02206-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02206-x","url":null,"abstract":"<p>Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35–50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, and colony formation. Additionally, RDAA facilitates tumor formation in fibroblast models, further underscoring its oncogenic potential in vivo. Importantly, RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors. Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors. Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4% (5/48) and 8.5% (100/1173) patients who were RDAA positive, respectively. Notably, among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment, five achieved objective response including two who experienced complete response (CR). Together, the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"122 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846502","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":"Cancer chemoprevention: signaling pathways and strategic approaches","authors":"Junling Ren, Guangli Yan, Le Yang, Ling Kong, Yu Guan, Hui Sun, Chang Liu, Lei Liu, Ying Han, Xijun Wang","doi":"10.1038/s41392-025-02167-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02167-1","url":null,"abstract":"<p>Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"8 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846510","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":"Environment impacts sexual preference: dopamine sends signals under pressure to decide which sex you like","authors":"Rou Li, Lin Liu, Min Wu","doi":"10.1038/s41392-025-02211-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02211-0","url":null,"abstract":"<p>A study by Wei et al. in <i>Science</i> identified a unique sexual binary neural circuit encoding a sexual preference switch, known as the ventral tegmental area dopaminergic (VTA^DA) circuit, which exhibits a preference for female social interactions among both sex mice, but switches to male preferences when confronted with survival threats (Fig. 1).¹</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-025-02211-0/MediaObjects/41392_2025_2211_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"816\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-025-02211-0/MediaObjects/41392_2025_2211_Fig1_HTML.png\" width=\"685\"/></picture><p><b>a</b> Schematic diagram illustrating the social preference test. Both male and female mice exhibited a preference for social interaction with females. However, this preference shifted to male preference when facing survival threats (TMT, contextual FC, or cued FC). <b>b</b> The sexually dimorphic DA circuits involve the sociosexual preferences of females and males. C-Fos staining revealed that the activity changes in VTA^DA and their downstream circuits, the mPOA and the NAc, are closely related to these changes. A calcium signaling fiber optic recording method for real-time monitoring of VTA^DA neural activity during social processes, along with a chemical genetics approach for activating VTA^DA neurons. Dual-color calcium signal fiber recording combined with viral tracing for synchronous monitoring of VTADA neuronal subpopulation activity. Chemical genetic methods were employed to manipulate the VTA^DA-mPOA and VTA^DA-NAc projection. The competitive balance between VTA^DA-NAc and the defense loop VTA^DA-mPOA determines the social preferences of male animals. By employing optogenetic techniques, the VTA-NAc projection was stimulated with light in both tonic and phasic discharge modes. Female individuals selectively regulate downstream neurons by modulating firing patterns in the VTA^DA-NAC) ultimately shaping their social preferences. TMT trimethylthiazoline, FC fear conditioning, VTA ventral tegmental area, mPOA midbrain preoptic area, NAc nucleus accumbens, CNO clozapine N-oxide, D1R type 1 DA receptor, D2R type 2 DA receptor. This figure was created with BioRender.com</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"6 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846500","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}