Signal Transduction and Targeted Therapy最新文献

{"title":"Astrocytic monoamine oxidase B (MAOB)–gamma-aminobutyric acid (GABA) axis as a molecular brake on repair following spinal cord injury","authors":"Hye Yeong Lee, Jung Moo Lee, Hye-Lan Lee, Jiyeon Park, Heeyoung An, Eun Kyung Park, Sae Yeon Hwang, Sol lip Yoon, Gwang Yong Hwang, Keung Nyun Kim, Min-Ho Nam, Seung Eun Lee, Hyunji Kang, Joungha Won, Bo Ko Jang, Elijah Hwejin Lee, SunYeong Choi, Mingu Gordon Park, Sang Wook Kim, Ki Duk Park, SeungHwan Lee, C. Justin Lee, Yoon Ha","doi":"10.1038/s41392-025-02398-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02398-2","url":null,"abstract":"<p>Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system (CNS) injury. The glial scar has been proposed as a major contributor to this failure in the regenerative process. However, its underlying molecular and cellular mechanisms remain unclear. Here, we report that monoamine oxidase B (MAOB)-dependent excessive γ-aminobutyric acid (GABA) release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) expression in severe spinal cord injury (SCI) animal models. Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery. Notably, the selective MAOB inhibitor, KDS2010, facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model. Its dose-dependent effects were further validated in a monkey SCI model. Moreover, KDS2010 demonstrated a tolerable safety profile and dose-proportional pharmacokinetics in healthy humans during a phase 1 clinical trial. This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury. Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"35 1","pages":"295"},"PeriodicalIF":39.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031912","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":"Neuroendocrine cells signal for repair: hedgehog leading the way","authors":"Mengjie Li, Mengmeng Zhou, Jin Jiang","doi":"10.1038/s41392-025-02386-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02386-6","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"59 1","pages":"291"},"PeriodicalIF":39.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031911","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":"Loss-of-function variations in solute carrier family 38 member 6 are associated with essential tremor","authors":"Zhangqi Yuan, Qiying Sun, Junyu Luo, Lu Zhang, Yichi Zhang, Jifeng Guo, Cheng Wang, Kangjuan Yang, Shumin Yang, Yanjie Cao, Yinhua Shen, Jiaming Cui, Hengxiang Cui, Hao Sun, Tingbin Ma, Xuan Xu, Chun-Jie Liu, Tao Wang, An-Yuan Guo, Aifang Cheng, Luoying Zhang, Jun Liu, Man Jiang, Beisha Tang, Jing Yu Liu","doi":"10.1038/s41392-025-02380-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02380-y","url":null,"abstract":"<p>Essential tremor (ET) is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity. Although numerous candidate genes and loci have been reported, the etiology of ET remains unclear. A novel ET-related gene was initially identified in a five-generation family via whole-exome sequencing, and other variants were identified in 772 familial ET probands and 640 sporadic individuals via whole-genome sequencing. Among 71 (9.18%) Chinese families and 47 (7.34%) sporadic individuals with ET, we identified 15 types of protein-altering variants in solute carrier family 38 member 6 (<i>SLC38A6)</i>, which encodes sodium-coupled neutral amino acid transporter 6 (SNAT6) and is inherited in an autosomal dominant pattern. Over-expression of mutant SNAT6 for the three most common human mutations (p.Y108F, p.M281T and p.G318S) significantly impaired L-arginine (L-Arg) uptake in HeLa cells. The homozygous <i>Slc38a6</i> deletion mice <i>(Slc38a6</i>^-/-) exhibited reduced L-Arg uptake in their cerebellar neurons, tremor, and cerebellar pathology. Slice electrophysiology revealed reduced neuronal Purkinje cell (PC) excitability and elevated inhibitory synaptic transmission in <i>Slc38a6</i>^-/- mice, in line with elevated “hairy” basket coverage around the PC soma. Furthermore, heterozygous <i>Slc38a6</i> deletion <i>(Slc38a6</i>^+/-) and PC-specific <i>Slc38a6</i> deletion (<i>Slc38a6</i>^PC-/-) mice also displayed tremor and PC abnormalities similar to those found in <i>Slc38a6</i>^-/- mice. These PCs displayed mitochondrial abnormalities and elevated ferroptosis markers (ACSL4, TFRC and Fe ions). In conclusion, we identified variants in <i>SLC38A6</i> that contribute ~8.35% to ET, generated mouse models displaying tremor, and delineated cerebellar cellular abnormalities and potential mechanisms underlying ET etiology.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"23 1","pages":"296"},"PeriodicalIF":39.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031913","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":"Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers","authors":"Gui-Zhen Wang, Zheng Wang, Shi-Hao Bai, Yun Tan, Wen-Zhao Zhong, Guo-Gui Sun, Yu-Tao Liu, Bo Pan, Chen Huang, Di Wang, Bei-Bei Sun, Dong-Ni Chen, Bin Zhang, Yong-Chun Zhou, Sheng Li, Xiang-Wei Zhang, Si-Chong Han, Fu-Ying Yang, Xue-Yan Shi, Xiao-Liang Jie, Yu-Ke Shen, Li-Jun Liang, Zhe-Sheng Wen, Li Zhang, Ming-Kun Li, Na Wang, Jin-song Liu, Ying Dong, Man-Li Wang, Yan Wang, Chang-Li Wang, Da-Wei Xie, Ze-Guang Han, Jian-Ming Ying, Chong Chen, Yun-Chao Huang, Hong-Bin Ji, Yuan-Yuan Zhang, Yan Yu, Guang-Biao Zhou","doi":"10.1038/s41392-025-02378-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02378-6","url":null,"abstract":"<p>Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the <i>ASCL1</i>⁺/<i>MKI67</i>⁺ and <i>ASCL1</i>⁺/<i>CRIP2</i>⁺ clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the <i>ASCL1</i>⁺<i>SOX1</i>⁺ stem-like cell cluster across SCLC subtypes. The major histocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focal adhesion kinase (FAK) splicing variants identified in 119 (77.3%) of 154 patients. FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models. Eleven high-frequency mutations were identified in addition to <i>TP53</i> and <i>RB1</i>, and smoking status and tumor stage did not affect microbiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicing variants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for this recalcitrant cancer.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"27 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025367","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":"Epidemiological and phylogenetic characteristics of human metapneumovirus in Beijing, China, 2014–2024","authors":"Aihua Li, Cheng Gong, Liang Wang, Yuling Han, Lu Kang, Geng Hu, Jian Cao, Maozhong Li, Xuejiao Guan, Ming Luo, Lei Yu, Yuchuan Li, Fang Huang, George F. Gao, Quanyi Wang","doi":"10.1038/s41392-025-02377-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02377-7","url":null,"abstract":"<p>In November 2024, there was an unusual surge in human metapneumovirus (hMPV) infection cases in Beijing. We performed an epidemiological investigation among cases with acute respiratory tract infection (ARTI). We enrolled ARTI cases from 35 sentinel hospitals, collected samples and medical records, conducted comprehensive pathogen testing, sequenced target genes or whole genomes, and performed phylogenetic analysis. A total of 79,793 cases were included in this study from 2014 to 2024. The hMPV epidemic exhibited typical seasonality from December to April of the following year, with an overall positivity rate of hMPV of 1.6%. The positivity rate of hMPV was highest in the 0–4 year age group (3.4%) and remained relatively high (1.2%) among populations over 60 years of age. Genotypes A and B were cocirculated, with predominant genotypes alternating every two years. We identified two variants of A2c with 180 or 111 nucleotide duplications in the G gene since 2016, and the A2c_111nt-dup has been predominant (56.9%) over the parent A2c since 2018. HMPV infection experienced an unusual surge beginning in November 2024 and peaked in December (9.5%). Subgenotype B2 (98.3%) returned to the predominant position instead of the A2c_111nt-dup and seemed to be associated with milder illness. Twenty hMPV isolates collected in 2024 were identified as known subgenotypes (A2c and B2) via whole-genome analyses. In conclusion, hMPV exhibited a typical seasonality in Beijing, with the predominant genotypes alternating every two years. Its unusual surge in November 2024 was attributed to the reoccurrence of hMPV B2 rather than a novel variant.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"71 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017544","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: Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis","authors":"Xuantong Zhou, Furong Huang, Gang Ma, Wenqing Wei, Nan Wu, Zhihua Liu","doi":"10.1038/s41392-025-02379-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02379-5","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/s41392-022-01199-1, published online 24 October 2022</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"24 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007227","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":"Targeting TRPV6/CXCR4 complexes prevents castration-resistant prostate cancer metastasis to the bone","authors":"Clément Cordier, Aurélien Haustrate, Adriana Mihalache, Erika Duval, Emilie Desruelles, Corentin Spriet, Baptiste Casel, Lotfi Slimani, Benjamin Soret, Laurent Allart, George Shapovalov, Pierre Gosset, Natalia Prevarskaya, V’yacheslav Lehen’kyi","doi":"10.1038/s41392-025-02376-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02376-8","url":null,"abstract":"<p>Bone metastasis most commonly occurs in castration-resistant prostate cancer (CRPC). The TRPV6 calcium channel is absent in healthy prostate tissue, but its expression increases considerably during cancer progression. We hypothesized that cancer cells induce TRPV6 expression de novo to directly benefit from tightly regulated calcium intake <i>via</i> TRPV6 while providing cancer cells with a selective advantage for metastasis in the calcium-abundant niche, such as bone. Using a cohort of prostate cancer tissue biopsies from patients with a clinical history of at least 10 years after biopsy, we report that TRPV6 expression directly correlates with CRPC tumor aggressiveness and increased risk of metastasis development. The TRPV6 channel is involved in the acquisition of both mesenchymal and invasive phenotypes through increased phosphorylation of CaMK2 followed by the translocation of the transcription factor NF-κB to the nucleus and the expression of EMT markers, MMPs, and transcription factors such as Twist, Snail, and Slug. Moreover, TRPV6 expression was accompanied by increased formation of CXCR4/TRPV6 complexes. In vivo, mice bearing <i>trpv6</i>^<i>+/+</i> tumors presented increased metastasis, notably bone metastasis, whereas <i>trpv6</i>^{<i>−/−</i>} mice developed no metastasis. Targeting TRPV6 with a monoclonal antibody resulted in a significant reduction in the metastatic burden and an increase in overall survival. When AMD3100, a selective inhibitor of the CXCR4 receptor, was combined with AMD3100, a synergistic effect on the suppression of metastasis development was achieved. Thus, the suppression of CRPC metastasis to bone can be achieved <i>via</i> simultaneous targeting of TRPV6/CXCR4, demonstrating that combined therapy is a proof-of-concept approach in vivo.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995698","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":"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}