Signal Transduction and Targeted Therapy最新文献

{"title":"Acevaltrate as a novel ferroptosis inducer with dual targets of PCBP1/2 and GPX4 in colorectal cancer.","authors":"Dianping Yu,Hongmei Hu,Qing Zhang,Chengji Wang,Mengting Xu,Hanchen Xu,Xiangxin Geng,Minchen Cai,Hongwei Zhang,Mengmeng Guo,Dong Lu,Hanchi Xu,Linyang Li,Xing Zhang,Ruling Shen,Sheng Lin,Qun Wang,Weidong Zhang,Sanhong Liu","doi":"10.1038/s41392-025-02296-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02296-7","url":null,"abstract":"Ferroptosis induced by ferrous ions (Fe2+) and lipid peroxidation accumulation is a novel form of regulated cell death that has become a hot topic in tumor therapy research. Identifying small-molecule drugs that can induce ferroptosis in tumor cells is a very attractive therapeutic strategy. Here, we screened a natural product, acevaltrate (ACE), which rapidly and strongly induces ferroptosis in colorectal cancer cells. ACE not only increases Fe2+ levels in colorectal cancer cells by targeting iron chaperones PCBP1/2 and reducing their expression but also disrupts the antioxidant system of colorectal cancer cells by targeting GPX4 and inhibiting its enzymatic activity, leading to its ubiquitin-mediated degradation. This dual effect of ACE makes it significantly more effective than classical ferroptosis inducers in inducing ferroptosis. Our animal experiments revealed that the therapeutic effect of ACE surpasses that of established ferroptosis-inducing drugs and is superior to that of first-line clinical drugs such as capecitabine and TAS-102. Importantly, ACE also demonstrated superior inhibitory effects in colorectal tumor organoids versus at the cellular level, underscoring its potential for clinical application. This study pioneers the discovery of a small molecule inhibitor that targets both PCBP1/2 and GPX4, offering a novel therapeutic strategy for eliminating cancer cells through ferroptosis. Acevaltrate (ACE) was identified as a potent inducer of ferroptosis in colorectal cancer cells. ACE increases Fe2+ levels by targeting PCBP1/2 and disrupts the antioxidant system by inhibiting GPX4, leading to its degradation. This dual action makes ACE more effective at inducing ferroptosis than traditional inducers. Our study introduces ACE as the first small-molecule inhibitor of PCBP1/2 and GPX4, offering a new therapeutic approach for cancer cell elimination through ferroptosis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"42 1","pages":"211"},"PeriodicalIF":39.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568615","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":"Tislelizumab (anti-PD-1) plus chemotherapy as neoadjuvant therapy for patients with stage IB3/IIA2 cervical cancer (NATIC): a prospective, single-arm, phase II study.","authors":"Jindong Sheng, Haitao Luo, Xiangyu Liu, Chunyan Liu, Wenhao Zhou, Yujie Zhao, Ruoyan Liu, Dan Li, Changxiao Xu, Bo Yang, Ying Liu, Xin Fu, Lewen Bao, Ke Wang, Jihui Hao, Wenxin Liu","doi":"10.1038/s41392-025-02294-9","DOIUrl":"10.1038/s41392-025-02294-9","url":null,"abstract":"<p><p>The clinical benefit of neoadjuvant immunochemotherapy in locally advanced cervical cancer (LACC) remains unclear. This single-arm, phase II study (Chinese Clinical Trial Registry, ChiCTR2200065392) aimed to evaluate the efficacy and safety of neoadjuvant anti-programmed cell death protein 1 (PD-1) antibody tislelizumab in combination with chemotherapy in treatment-naïve patients with stage IB3/IIA2 LACC. Enrolled patients received tislelizumab (200 mg, every 3 weeks) plus chemotherapy for 3 cycles before radical surgery. The primary endpoint was the pathological complete response (pCR). Secondary endpoints were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1, disease-free survival, overall survival, and safety. Exploratory endpoints included tissue-based and blood-based biomarkers to identify the biological drivers behind the clinical outcomes. Between November 2022 and March 2024, 30 patients were enrolled. All patients completed 3 cycles of neoadjuvant immunochemotherapy and underwent radical surgery. The pCR was observed in 20 (66.7%) patients, and 4 (13.3%) patients achieved major pathological response (MPR), with an optimal pathological response rate (OPR) of 80.0%. The ORR was 90.0%, with 17 (56.7%) complete responses. Survival data were immature at the median follow-up of 14.7 months (data cutoff, December 31, 2024). Grade 3 treatment-related adverse events (TRAEs) and immune-related AEs occurred in 26.7% and 3.3% of patients, respectively. No treatment-related death occurred. Patients with pCR had significantly higher expression of PD-L1 CPS at baseline, and a strong relationship with immune-related signature (all p < 0.05). Neoadjuvant tislelizumab plus chemotherapy showed promising antitumor efficacy and a well-tolerated safety profile in patients with stage IB3/IIA2 LACC, and might be a potential option in this population.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"215"},"PeriodicalIF":40.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12227751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR-T cell therapy for cancer: current challenges and future directions.","authors":"Inés Zugasti, Lady Espinosa-Aroca, Klaudyna Fidyt, Vladimir Mulens-Arias, Marina Diaz-Beya, Manel Juan, Álvaro Urbano-Ispizua, Jordi Esteve, Talia Velasco-Hernandez, Pablo Menéndez","doi":"10.1038/s41392-025-02269-w","DOIUrl":"10.1038/s41392-025-02269-w","url":null,"abstract":"<p><p>Chimeric antigen receptor T (CAR-T) cell therapies have transformed the treatment of relapsed/refractory (R/R) B-cell malignancies and multiple myeloma by redirecting activated T cells to CD19- or BCMA-expressing tumor cells. However, this approach has yet to be approved for acute myeloid leukemia (AML), the most common acute leukemia in adults and the elderly. Simultaneously, CAR-T cell therapies continue to face significant challenges in the treatment of solid tumors. The primary challenge in developing CAR-T cell therapies for AML is the absence of an ideal target antigen that is both effective and safe, as AML cells share most surface antigens with healthy hematopoietic stem and progenitor cells (HSPCs). Simultaneously targeting antigen expression on both AML cells and HSPCs may result in life-threatening on-target/off-tumor toxicities such as prolonged myeloablation. In addition, the immunosuppressive nature of the AML tumor microenvironment has a detrimental effect on the immune response. This review begins with a comprehensive overview of CAR-T cell therapy for cancer, covering the structure of CAR-T cells and the history of their clinical application. It then explores the current landscape of CAR-T cell therapy in both hematologic malignancies and solid tumors. Finally, the review delves into the specific challenges of applying CAR-T cell therapy to AML, highlights ongoing global clinical trials, and outlines potential future directions for developing effective CAR-T cell-based treatments for relapsed/refractory AML.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"210"},"PeriodicalIF":40.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid","authors":"Yanmei Zhang, Zheng Xiang, Yan Xu, Lo Sha Cheung, Xiwei Wang, Manni Wang, Howard Ho Wai Wong, Zhenyao Zhu, Wenyue Zhang, Yifan Gao, Xianze Luo, Yin Celeste Cheuk, Yixin Zhou, Xianfeng Zha, Yashi Chen, Man Li, Feifei Luo, Yiwei Chu, Yu-Lung Lau, Yinping Liu, Wenwei Tu","doi":"10.1038/s41392-025-02295-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02295-8","url":null,"abstract":"<p>Dietary fatty acids (FAs) are associated with the therapeutic intervention under various health conditions. Human γδ-T cells are indispensable for immunosurveillance toward malignant cells. However, their impact on γδ-T cell metabolism and function remains poorly unexplored. Here, we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid (PA) or oleic acid (OA) levels were associated with the efficacy of Vγ9Vδ2-T cell therapy. We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules, whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells. Mechanistically, we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ, which in turn induces cell pyroptosis, ultimately resulting in decreased antitumor activity. In contrast, OA reduces IFNγ secretion and mitigates cell pyroptosis, thereby restoring their antitumor activity. Alternatively, direct blockade of IFNγ by anti-IFNγ mAb or inhibition of pyroptosis by dimethyl fumarate (DMF) also restores their antitumor activity. This study highlights a novel mechanism whereby dietary FAs modulate γδ-T cell function through regulating IFNγ-mediated pyroptosis. Additionally, it offers proof-of-concept for an innovative approach by targeting IFNγ-mediated pyroptosis or dietary OA supplementation to strengthen the antitumor immunity of γδ-T cells against cancers.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"27 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547181","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":"Safety and immunogenicity of an HIV vaccine trial with DNA prime and replicating vaccinia boost.","authors":"Ying Liu,Wei Lv,Pu Shan,Dan Li,Ying-Qi Wu,You-Chun Wang,Yuan-Yuan Li,Qiang Liu,Jian-Sheng Wang,Yan-Ling Hao,Yong Liu,Wei-Jin Huang,Li Ren,Shu-Hui Wang,Tai-Sheng Li,Jing Xu,Yi-Ming Shao","doi":"10.1038/s41392-025-02259-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02259-y","url":null,"abstract":"Developing a safe and effective vaccine remains a global priority for ending the human immunodeficiency virus (HIV) pandemic. All HIV vaccine trials with protein, DNA, non-replication vector or their combinations failed in the past. We constructed the HIV-1 CN54 env, gag, and pol genes into both DNA and replicating vaccinia virus Tiantan vectors. In phase Ia, 12 healthy adults were given high (n = 6) or low (n = 6) doses of recombinant vaccinia virus Tiantan vaccine (rTV), to test its safety dose. In phase Ib, 36 healthy adults were assigned to the DNA (n = 6), DNA-L/rTV (n = 12), DNA-H/rTV (n = 12), and placebo (n = 6) groups. The DNA vaccine was injected intramuscularly at weeks 0, 4, and 8 and rTV with a bifurcated needle at week 12. All vaccines tested were safe and well-tolerated; most of the adverse events (AEs) were mild to moderate. The most commonly observed AEs were redness and papule at rTV vaccination sites and axillary enlarged lymph nodes at the same rTV vaccination arm. Smaller cutaneous lesions and shorter healing time were observed in smallpox vaccine experienced subjects. The DNA prime-rTV boost regimen induced anti-gp120 IgG and polyfunctional CD4+ T cells. No significant differences of anti-HIV IgG and T cell responses were found between the two prime-boost groups with high and low DNA doses. Moreover, smallpox vaccine naïve subjects elicited higher T cell responses and anti-gp120 antibodies. The result of this trial supports further development of HIV vaccine with DNA and replicating vaccinia vector for advanced clinical trials.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"27 1","pages":"208"},"PeriodicalIF":39.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533398","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":"Signaling pathways and targeted therapy for pulmonary hypertension","authors":"Joseph Adu-Amankwaah, Yue Shi, Hequn Song, Yixuan Ma, Jia Liu, Hao Wang, Jinxiang Yuan, Kun Sun, Qinghua Hu, Rubin Tan","doi":"10.1038/s41392-025-02287-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02287-8","url":null,"abstract":"<p>Pulmonary hypertension (PH) is a global health issue characterized by high mortality. The main targets for current therapies in PH focus on the prostacyclin, nitric oxide, and endothelin pathways. While the approaches targeting these pathways form the foundation of standard PH treatment, the challenge remains to develop more effective therapeutic strategies. Evidence of pathological characteristics in PH illustrates other cell signaling pathways that also participate in the proliferation, apoptosis, extracellular matrix remodeling, mitochondrial dysfunction, inflammation, endothelial-to-mesenchymal transition, ferroptosis, pyroptosis, and the intricate network of cell-cell interactions of endothelial cells, smooth muscle cells, fibroblasts, and macrophages. In this review, we explore the roles of twenty key signaling pathways in PH pathogenesis. Furthermore, the crosstalks among some pathways offer a more detailed understanding of the complex mechanisms of PH. Considering the crucial role of signaling pathways in PH progression, targeting these aberrant signaling or their hub molecules offers great potential for mitigating PH pathology. This review delves into a variety of therapeutic approaches for PH that target critical signaling pathways and network interactions, including gene therapy, cell therapy, and pharmacological interventions. Supported by evidence from both animal studies and clinical trials, these strategies aim to reverse pathological alterations in pulmonary vessels and restore their normal function, addressing the significant health challenges associated with PH.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"51 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520881","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":"Modification of lysine residues in proteins: a novel posttranslational effect of vitamin C","authors":"Dieter Kabelitz","doi":"10.1038/s41392-025-02288-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02288-7","url":null,"abstract":"<p>In a recent article published in <i>Cell</i>, He and colleagues reported that vitamin C (VitC) modifies lysine residues in proteins and peptides, thereby forming vitcyl-lysine, a process they have called vitcylation. They show that vitcylation of signal transducer and activator of transcription-1 (STAT1) increases its phosphorylation and thereby promotes interferon pathway activation in cancer cells and anti-tumor immunity.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515538","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":"Serine/threonine/tyrosine kinase 1 drives pancreatic carcinogenesis via GSK3β sequestration-mediated Wnt/β-catenin pathway hyperactivation","authors":"Cefan Zhou, Xueying Dong, Shi Li, Yue Xi, Yuan Liu, Xuehong Qian, Ziyan Song, Li Zhou, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Weiyong Liu, Yan Xiong, Zhentian Wang, Chaojun Yan, Zijian Zhang, Haichuan Zhu, Xing-Zhen Chen, Zhiyin Song, Jingfeng Tang","doi":"10.1038/s41392-025-02292-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02292-x","url":null,"abstract":"<p>The Wnt/β-catenin pathway is strongly relevant to pancreatic cancer progression, poor prognostic outcomes, and elevated cancer-related mortality. However, the mechanism underlying continuously activated Wnt/β-catenin signaling in pancreatic cancer, a context in which adenomatous polyposis coli (APC) mutations are rarely observed, remains poorly understood. In this study, we investigated the role of STYK1 in regulating canonical Wnt/β-catenin signaling and pancreatic cancer tumorigenesis using the <i>LSL-Kras</i>^<i>G12D</i>; <i>Trp53</i>^{<i>R172H/+</i>}; <i>Pdx1</i>^<i>Cre</i> mouse model. Our findings demonstrate that STYK1 directly binds to β-catenin and GSK3β, inhibiting GSK3β activity by increasing the level of its kinase-inactive form, which is phosphorylated at S9, and promoting its sequestration into MVBs. We further showed that STYK1-mediated GSK3β sequestration is impaired by autophagy inhibitors or in ATG7 knockout cells, linking this process to autophagic regulation. Structural analysis identified conserved tyrosine-based (Y191QRL194) and dileucine-based (GDLL203-204) sorting motifs in STYK1, which facilitate clathrin/AP2-dependent internalization essential for GSK3β sequestration. The phosphorylation of STYK1 at Y191 by BLK kinase enhances its interaction with AP2, thereby accelerating GSK3β sequestration and subsequent Wnt/β-catenin pathway activation. Notably, inhibitory peptides targeting either the STYK1-β-catenin or the STYK1-GSK3β interface significantly suppressed pancreatic cancer development in vitro and in vivo, underscoring their therapeutic potential. Collectively, these results elucidate a novel STYK1-driven mechanism for Wnt/β-catenin activation in APC-independent pancreatic cancer and provide preclinical evidence for targeting STYK1-mediated signaling as a therapeutic strategy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515542","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":"Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis","authors":"Martina Lepore Signorile, Elisabetta Di Nicola, Giovanna Forte, Paola Sanese, Candida Fasano, Vittoria Disciglio, Katia De Marco, Marialaura Latrofa, Loris De Cecco, Marica Ficorilli, Marta Lucchetta, Erica Torchia, Chiara Dossena, Giusy Bianco, Vito Spilotro, Claudia Ferroni, Nicoletta Labarile, Raffaele Armentano, Francesco Albano, Anna Mestice, Gianluigi Gigante, Valerio Lantone, Giuliano Lantone, Leonardo Vincenti, Alberto Del Rio, Greta Varchi, Valentina Grossi, Cristiano Simone","doi":"10.1038/s41392-025-02290-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02290-z","url":null,"abstract":"<p>Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) chemoresistance, recurrence, and metastasis. Therefore, identifying molecular stemness targets that are involved in tumor growth is crucial for effective treatment. Here, we performed an extensive in vitro and in vivo molecular and functional characterization, revealing the pivotal role of the lysine methyltransferase SET and MYND Domain Containing 3 (SMYD3) in colorectal cancer stem cell (CRC-SC) biology. Specifically, we showed that SMYD3 interacts with and methylates c-MYC at K158 and K163, thereby modulating its transcriptional activity, which is implicated in stemness and colorectal malignancy. Our in vitro data suggest that SMYD3 pharmacological inhibition or its stable genetic ablation affects the clonogenic and self-renewal potential of patient-derived CRC-SCs and organoids by altering their molecular signature. Moreover, we found that SMYD3 stable knock-out or pharmacological inhibition drastically reduces CRC tumorigenicity in vivo and CRC-SC metastatic potential. Overall, our findings identify SMYD3 as a promising therapeutic target acting directly on c-MYC, with potential implications for countering CRC-SC proliferation and metastatic dissemination.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"46 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515546","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":"The mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) enhances bone formation","authors":"Juliane Lehmann, Hui Lin, Zihao Zhang, Maren Wiermann, Albert M. Ricken, Franziska Brinkmann, Jana Brendler, Christian Ullmann, Luisa Bayer, Sandra Berndt, Anja Penk, Nadine Winkler, Franz Wolfgang Hirsch, Thomas Fuhs, Josef Käs, Peng Xiao, Torsten Schöneberg, Martina Rauner, Jin-Peng Sun, Ines Liebscher","doi":"10.1038/s41392-025-02291-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02291-y","url":null,"abstract":"<p>Osteoporosis represents an increasing health and socioeconomic burden on aging societies. Current therapeutic options often come with potentially severe side effects or lack long-term efficacy, highlighting the urgent need for more effective treatments. Identifying novel drug targets requires a thorough understanding of their physiological roles. Genome-wide association studies in humans have linked gene variants of the adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) to variations in bone mineral density and body height. In this study, we explore the impact of GPR133/ADGRD1 on osteoblast differentiation and function. Constitutive and osteoblast-specific knockouts of <i>Gpr133/Adgrd1</i> in mice lead to reduced cortical bone mass and trabecularization in the femurs and vertebrae — features characteristic of osteoporosis. This osteopenic phenotype in receptor-deficient mice is caused by impaired osteoblast function, which, in turn, promotes increased osteoclast activity. At the molecular level, GPR133/ADGRD1 regulates osteoblast function and differentiation through a combined activation mechanism involving interaction with its endogenous ligand, protein tyrosine kinase 7 (PTK7), and mechanical forces. This is demonstrated in vitro through stretch assays and in vivo via a mechanical loading experiment. Further in vitro analysis shows that GPR133/ADGRD1-mediated osteoblast differentiation is driven by cAMP-dependent activation of the β-catenin signaling pathway. Activation of GPR133/ADGRD1 with the receptor-specific ligand AP-970/43482503 (AP503) enhances osteoblast function and differentiation, both in vitro and in vivo, significantly alleviating osteoporosis in a mouse ovariectomy model. These findings position GPR133/ADGRD1 as a promising therapeutic target for osteoporosis and other diseases characterized by reduced bone mass.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"26 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515541","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}