Signal Transduction and Targeted Therapy最新文献

{"title":"Bone marrow B lymphopoiesis accelerates early cerebral amyloid pathology.","authors":"Jing Zhang,Wenting Fang,Hanchen Liu,Ran Li,Zhibao Zhu,Xin Wu,Shaobo Yao,Ying Fu,Rui Li,Wanjin Chen,Qinyong Ye,Qiang Liu,Xiaochun Chen","doi":"10.1038/s41392-025-02419-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02419-0","url":null,"abstract":"Bone marrow is a major source of hematogenous cells that orchestrate brain immunity. However, alterations in the bone marrow hematopoietic system in patients with Alzheimer's disease (AD) and their potential impacts on neuroinflammation and cerebral β-amyloid (Aβ) pathology remain unknown. Here, we report that Aβ accumulates within the bone marrow of patients with AD and is particularly concentrated in the central nervous system-surrounding bones. In 5 × FAD and APP/PS1 mice, two classic mouse AD models, Aβ accumulates within the skull bone marrow prior to substantial cerebral Aβ deposits. Flow cytometry and cell tracking analyses demonstrated that these AD mice exhibit enhanced bone marrow hematopoiesis in B lymphoid lineages, specifically an increase in age-associated B cells (ABCs), accompanied by heightened output of these cells into the brain parenchyma. Furthermore, intracranial Aβ injection into IL-6 knockout mice revealed that Aβ promotes B lymphocyte generation, particularly ABCs, via IL-6 signaling. Single-cell sequencing analysis following intracerebroventricular ABCs injection, combined with in vitro microglial culture studies, demonstrated that bone marrow-derived ABCs directly augment microglial reactivity, ultimately exacerbating Aβ neuropathology and cognitive deficits in AD models. Notably, blockade of IL-6R restricts B-cell activity and ABCs in the bone marrow, delays cerebral Aβ pathology and improves cognition. Our findings reveal the potential involvement of bone marrow-derived B cells in the early cerebral amyloid pathology in two mouse AD models and suggest that these B cells may serve as potential therapeutic candidates for patients with AD.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"89 1","pages":"312"},"PeriodicalIF":39.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078052","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":"EchoBack-CAR T cells: a sonogenetic solution to the persistent challenges of solid tumor immunotherapy.","authors":"Kiseok Han,Jung-Soo Suh,Tae-Jin Kim","doi":"10.1038/s41392-025-02387-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02387-5","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"221 4 1","pages":"304"},"PeriodicalIF":39.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078053","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":"Pantothenate kinase 4 controls lipid synthesis for T-cell proliferation by modulating coenzyme A and glutaminolysis.","authors":"Jeong-Ryul Hwang,Chi Thi Ngoc Nguyen,Gwanghoon Ko,Jung-Ah Kang,Yeongseon Byeon,Seowoo Park,Ryunha Chang,Dawoon Jung,Mi Yeon Jeon,Young Hoon Sung,Cho-Rong Lee,Ki-Hoan Nam,Je Kyung Seong,Sankar Ghosh,Yun Pyo Kang,Sung-Gyoo Park","doi":"10.1038/s41392-025-02385-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02385-7","url":null,"abstract":"During T-cell-mediated inflammatory responses, T cells are activated upon recognizing specific antigens presented by antigen-presenting cells. This recognition initiates signaling through the TCR and CD28, leading to their activation and subsequent clonal expansion. Within the signaling cascades triggered by TCR and CD28 engagement, the CD28-PI3K pathway serves as a central regulator of metabolic reprogramming in T cells, supporting the biosynthetic needs essential for their effective proliferation. In this study, we found that the regulation of PANK4 plays a role in TCR/CD28-mediated CD4+ T-cell proliferation by regulating de novo lipid synthesis. The CD28 signaling pathway negatively regulates PANK4 through direct binding with PDK1, thereby controlling de novo lipid synthesis for CD4+ T-cell proliferation. Interestingly, we found that Pank4-deficient CD4+ T cells enhance coenzyme A synthesis and glutaminolysis, whereby glutamine contributes carbon for fatty acid synthesis and provides nitrogen for coenzyme A biosynthesis. The regulatory role of PANK4 in CD4+ T-cell proliferation was confirmed in models of experimental colitis and influenza A virus infection, where Pank4-deficient CD4+ T cells exhibited greater expansion than their wild-type counterparts when co-transferred. Our findings suggest that PANK4 regulation of de novo lipid synthesis is crucial for TCR/CD28-induced CD4+ T-cell proliferation and represents a potential target for modulating general CD4+ T-cell responses.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"38 1","pages":"302"},"PeriodicalIF":39.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078057","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":"Reversion of aortic valve cells calcification by activation of Notch signalling via histone acetylation induction.","authors":"Gloria Garoffolo,Silvia Ferrari,Sara De Martino,Emanuele Pizzo,Veronica Candino,Lavinia Curini,Federica Macrì,Boudewijn P T Kruithof,Alessia Mongelli,Magda Grillo,Nadia Fanotti,Pamela Fejzaj,Manuel Casaburo,Azizah Alanazi,Nina Ajmone Marsan,Feras Khaliel,Ahmed Alsulbud,Marco Agrifoglio,Gualtiero I Colombo,Mattia Chiesa,Antonella Farsetti,Carlo Gaetano,Angela Raucci,Maurizio Pesce","doi":"10.1038/s41392-025-02411-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02411-8","url":null,"abstract":"Calcification of the aortic valve is a prevalent cardiovascular pathology in the aging population. Traditionally linked to inflammation, lipid accumulation, and risk conditions, this disease remains poorly understood, and effective treatments to halt its progression are not yet available. We hypothesized that calcification of the human valve interstitial cells (VICs) is associated with cellular senescence and alterations in the epigenetic setup, like in arteries. To verify this hypothesis, we examined the epigenetic marks (DNA methylation; Histones H3/H4 acetylation/methylation), the senescence and the calcification process in human VICs obtained from two distinct pathologic settings of the aortic valve (valve insufficiency and valve stenosis), and employed a mouse model of vascular/valve calcification, based on the administration of Vitamin D. Our findings revealed a link between the senescent phenotype of human VICs and calcification, characterized by increased DNA methylation and changes in histone epigenetic marks. To reverse the senescent/calcific VICs phenotype, we used Pentadecylidenemalonate-1b (SPV106), which activates KAT2B/pCAF histone acetyltransferase. In human VICs, SPV106 restored Histone acetylation marks, modified general chromatin accessibility and upregulated expression of Notch1, a potent inhibitor of valve calcification. The treatment also prevented the accumulation of calcific lesions in an ex vivo model of aortic valve calcification. In vivo treatment with SPV106 reduced calcification of the valve induced by administering Vitamin-D and positively preserved the valve motion compromised by calcification and the overall cardiac function. Based on these results, we propose the treatment with activators of histone acetylates as a viable option to prevent senescence/calcification of aortic VICs via restoration of correct chromatin acetylation, with concrete hopes to retard the progression of valve stenosis, a still largely unmet therapeutic need.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"155 1","pages":"311"},"PeriodicalIF":39.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078051","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":"GPR15 differentially regulates the effects of cigarette smoke exposure on Crohn's disease and ulcerative colitis.","authors":"Luhua Gao,Huaping Zheng,Qing Zhao,Yubin Wang,Yong He,Can Hou,Na Yang,Kun Liang,Wenjian Meng,Xuefei He,Kun Zheng,Wenning Tian,Jiacheng Zhang,Ting Zhang,Hui Mao,Liming Zhang,Jingyu Zhang,Jingqiu Cheng,Jürgen Brosius,Huan Song,Yuchuan Huang,Yi Chen,Cheng Deng","doi":"10.1038/s41392-025-02384-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02384-8","url":null,"abstract":"Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder characterized by gastrointestinal inflammation. Cigarette smoke is a well-established risk factor for the development and exacerbation of CD while exerting a paradoxical protective effect against the onset of UC. The exact mechanisms by which cigarette smoke influences IBD, as well as the opposite effects in UC and CD, have long remained unexplained. Here, we demonstrated the detrimental impact of cigarette smoke on CD progression while highlighting its beneficial effects on UC, as evidenced by analyses of human sample data. Mouse models of CD and UC exposed to cigarette smoke presented phenotypes consistent with those observed in human disease. GPR15, previously reported to direct regulatory T (Treg) cell colon homing, was upregulated in the colon tissues of both chemically induced colitis models after smoke exposure. Importantly, Gpr15 deletion ameliorated smoke-induced CD while increasing UC severity in mice. Furthermore, our study revealed that cigarette smoke mediated GPR15 to amplify colonic T helper type 17 (Th17) cell populations, thereby worsening the adverse effects of smoking on CD in mouse models. Moreover, cigarette smoke induced an increase in Treg cells through GPR15, which contributed to mitigating its impact on UC in mouse models. Moreover, in cigarette smoke-exposed CD and UC model mice, C57BL/6JGpt-Tg (human GPR15) transgenic mice presented phenotypes opposite those of Gpr15-deficient mice. Overall, our study offers mechanistic insights into the role of cigarette smoke-induced GPR15+ T cells in mediating the divergent effects of smoking on UC and CD.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"83 1","pages":"306"},"PeriodicalIF":39.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071862","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":"Anlotinib plus sintilimab as first-line treatment for patients with advanced colorectal cancer (APICAL-CRC): an open-label, single-arm, phase II trial","authors":"Zhan Wang, Bao-Dong Qin, Chen-Yang Ye, Miao-Miao Wang, Ling-Yan Yuan, Hou-Shan Yao, Xiao-Dong Jiao, Ke Liu, Wen-Li Zhou, Wen-Xing Qin, Li Sun, Wei-Ping Dai, Yan Ling, Ying Wu, Shi-Qi Chen, Ying-Fu Zhang, Dong-Min Shi, Xiao-Peng Duan, Xue Zhong, Xi He, Wen-Xin Zhai, Bei Zhang, Da-Dong Zhang, Ning Gao, Yuan-Sheng Zang","doi":"10.1038/s41392-025-02383-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02383-9","url":null,"abstract":"<p>This is an investigator-initiated, open-label, single-arm, phase II trial that aimed to assess the combination of sintilimab plus anlotinib among patients with treatment-naïve metastatic colorectal cancer (mCRC) (APICAL-CRC ClinicalTrials.gov number, NCT04271813). Between June 2020 and September 2023, a total of 30 patients were eventually enrolled and received the study regimen. Among these 30 patients, 50% had an Eastern Cooperative Oncology Group(ECOG) score of 0–1, and the other 50% had a score of 2. The objective response rates (ORRs) were 48.3% (95% CI 29.4–67.5) in the efficacy-evaluable cohort and 46.7% (95% CI 28.3–65.7) in the intent-to-treat (ITT) cohort. Twelve patients had stable disease, and the disease control rates (DCRs) were 89.7% (95% CI 72.6–97.8) and 86.7% (95% CI 69.3–96.2) in the efficacy-evaluable and ITT cohorts, respectively. The median progression-free survival (mPFS) was 8.6 months (95% CI 4.8–11.0), and the median overall survival (mOS) reached 22.9 months (95% CI 13.5–36.3). Treatment-related adverse events (TRAEs) of any grade were reported in 23 patients (76.7%), and grade 3 TRAEs occurred in 4 patients (13.3%). Multivariate Cox regression analysis revealed that the presence of liver metastases was an independent prognostic factor for poor PFS (HR = 5.66, 95% CI 1.58–20.2) and OS (HR = 7.85, 95% CI 1.38–44.8), whereas <i>FLT</i> mutation was independently associated with poor OS(HR = 12.5, 95% CI 1.54–101). This trial demonstrated that sintilimab plus anlotinib exhibited promising antitumor efficacy along with a manageable safety profile among treatment-naïve mCRC patients.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"35 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068050","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":"CABIN1 peptide effectively targets MEF2D-fusion protein in B-cell precursor acute lymphoblastic leukemia.","authors":"Subin Cha,Sangho Lee,Han-Teo Lee,Hyonchol Jang,Hong-Duk Youn","doi":"10.1038/s41392-025-02397-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02397-3","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"87 1","pages":"294"},"PeriodicalIF":39.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058938","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":"Coinhibition of the MEK/RTK pathway has high therapeutic efficacy in KRAS-mutant non-small cell lung cancer","authors":"Jun Lu, Minjuan Hu, Yikai Zhao, Tianqing Chu, Wei Zhang, Yijia Zhou, Xinlei Cai, Jun Wu, Liang Hu, Chunlei Shi, Liwen Xiong, Aiqin Gu, Huimin Wang, Yanwei Zhang, Yuqing Lou, Runbo Zhong, Zhiqiang Gao, Hongyu Liu, Chao Zhou, Yingli Wu, Liang Zhu, Hua Zhong, Hongbin Ji, Baohui Han","doi":"10.1038/s41392-025-02382-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02382-w","url":null,"abstract":"<p>Oncogenic KRAS mutations are frequently detected in NSCLC. It remains a major challenge to target all KRAS mutants. MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC; however, their easy adaptive resistance precludes further application. Here, we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC. Furthermore, we evaluated this strategy in a clinical study (NCT04967079) involving 33 advanced non-G12C KRAS-mutant NSCLC patients. The phase Ia containing 13 patients showed that the recommended phase 2 dose (RP2D) is trametinib (2 mg) plus anlotinib (8 mg), the objective response rate (ORR) is 69.2% (95% CI: 38.6-90.9), the median progression-free survival (PFS) is 6.9 months (95% CI: 3.9 to could not be evaluated), disease control rate (DCR) is 92% (95% CI: 64.0–99.8) and the rate of adverse events (AEs) ≥grade 3 is 23%. The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D, with the ORR at 65% (95% CI: 40.8–84.6), the median PFS is 11.5 months (95% CI: 8.3–15.5), the median overall survival (OS) is 15.5 months (95% CI: 15.5 to could not be evaluated), the DCR at 100% (95% CI: 83.2–100.0), the median duration of overall response (DoR) is 9.3 months (95% CI: 2.5–12.1), and the rate of AEs ≥ grade 3 at 35%. Overall, this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"74 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035154","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":"Inhibition of salt-inducible kinases resolves autoimmune arthritis by promoting macrophage efferocytosis","authors":"Mingyu Lee, Min Kyung Kim, Shenzheng Mo, Yoe-Sik Bae, Hong-Hee Kim","doi":"10.1038/s41392-025-02381-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02381-x","url":null,"abstract":"<p><b>Dear Editor</b>,</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"62 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035153","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":"Rewiring β2-adrenergic receptor signaling: harnessing non-canonical GRK functions to treat metabolic diseases","authors":"Sean A. Cullum, Andreas Bock","doi":"10.1038/s41392-025-02407-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02407-4","url":null,"abstract":"<p>In a study published recently in <i>Cell</i>, Motso et al.¹ developed a series of G protein-coupled receptor kinase 2 (GRK2)-biased agonists for the β₂-adrenergic receptor (β₂AR) which showed efficacy in stimulating muscular glucose uptake without eliciting cardiac side effects typically associated with systemically applied β-agonists.² The candidate drug, compound 15, was well-tolerated in a phase 1 clinical trial and could provide a promising alternative treatment option for type 2 diabetes and obesity.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"7 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035152","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}