Signal Transduction and Targeted Therapy最新文献

{"title":"Mitochondrial metabolism and cancer therapeutic innovation.","authors":"Hongxiang Du,Tianhan Xu,Sihui Yu,Sufang Wu,Jiawen Zhang","doi":"10.1038/s41392-025-02311-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02311-x","url":null,"abstract":"Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":"245"},"PeriodicalIF":39.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769576","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":"mTOR inhibition sensitizes T-ALL cells to Venetoclax through engagement of the integrated stress response.","authors":"Loredana Urso,Irene Bertazzolo,Alberto Corradin,Micol Silic-Benussi,Sonia A Minuzzo,Donna M D'Agostino,Vincenzo Ciminale","doi":"10.1038/s41392-025-02368-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02368-8","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"77 6 1","pages":"246"},"PeriodicalIF":39.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769577","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":"Epigenetic regulation of cancer stemness","authors":"Claudia Galassi, Gwenola Manic, Manel Esteller, Lorenzo Galluzzi, Ilio Vitale","doi":"10.1038/s41392-025-02340-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02340-6","url":null,"abstract":"<p>Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators, as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks. Such alterations (i.e., methylation, acetylation, and ubiquitination) are catalyzed by an array of dedicated enzymes with antagonistic activity, including methyltransferases and demethylases, acetyltransferases and deacetylases, as well as ubiquitin ligases and deubiquitinating enzymes. The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues. In line with this notion, epigenetic defects have been associated with a variety of human disorders, including (but not limited to) congenital conditions as well as multiple hematological and solid tumors. Here, we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness, i.e., the ability of a small population of poorly differentiated malignant cells to (1) self-renew while generating a more differentiated progeny, and (2) exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress. Moreover, we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"31 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756362","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 AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma","authors":"Qi Wang, Juan Liu, Ming Yang, Jun Zhou, Yaxuan Li, Jingjing Zheng, Hao Jia, Shuhua Yue, Yinpeng Le, Yuxin Su, Wenrui Ma, Ni An, Yunfang Wang, Jiahong Dong","doi":"10.1038/s41392-025-02321-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02321-9","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and resistance to systemic therapies remains a significant clinical challenge. This study investigated the mechanisms by which metabolic reprogramming contributes to systemic treatment resistance in HCC. We established HCC cell lines with multidrug resistance characteristics and observed enhanced metabolic activity in these cells. Integrated multiomics analyses revealed hyperactive glucose‒lipid and glutathione metabolic pathways that play critical roles in supporting tumor cell proliferation and survival. We constructed a metabolic reprogramming atlas for HCC-resistant cells and identified aldo-keto reductase (Aldo-keto reductase family 1 Member B1, AKR1B1) as a key regulator of this reprogramming, which sustains drug resistance by regulating energy metabolism and enhancing stress tolerance. Importantly, AKR1B1 expression levels are closely associated with drug resistance and poor prognosis in HCC patients. The secretory nature of AKR1B1 not only underscores its predictive value but also facilitates the intercellular transmission of drug resistance. In terms of overcoming resistance, the AKR1B1 inhibitor epalrestat significantly mitigated drug resistance when it was used in combination with standard therapies. These findings underscore the importance of metabolic reprogramming in the development of HCC resistance. AKR1B1, a key enzyme that regulates metabolic reprogramming, has been identified as a potential biomarker and therapeutic target, providing new insights into overcoming resistance in HCC treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"50 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756379","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":"Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches","authors":"Muhammad Tufail, Can-Hua Jiang, Ning Li","doi":"10.1038/s41392-025-02280-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02280-1","url":null,"abstract":"<p>Immune evasion represents a significant challenge in oncology. It allows tumors to evade immune surveillance and destruction, thereby complicating therapeutic interventions and contributing to suboptimal patient outcomes. This review addresses the critical need to understand how cancers evade immune surveillance. It aims to provide a comprehensive overview of strategies of tumors to escape immune detection by examining tumor-induced immune suppression, immune checkpoint regulation, and genetic and epigenetic influences. Moreover, it explores the dynamic role of the tumor microenvironment (TME) in fostering immune resistance and highlights the impact of metabolic reprogramming on immune suppression. Additionally, this review focuses on how tumor heterogeneity influences immune evasion and discusses the limitations of current immunotherapies. The role of key signaling pathways, including programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), transforming growth factor-β (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS–STING) is analyzed to elucidate their contributions to immune escape. Emphasizing the complexities of immune evasion, this review underscores the importance of personalized approaches and the integration of multi-omics data to combat therapeutic resistance. Furthermore, it discusses novel and emerging therapeutic strategies, such as bispecific antibodies, oncolytic viruses, and nanotechnology-driven immunotherapies, showcasing innovative avenues in cancer treatment. The significance of this review lies in its potential to guide future research and innovations in immunotherapy, ultimately improving patient outcomes and advancing our understanding of cancer immunology.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"54 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747431","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":"Impact of allogeneic dental pulp stem cell injection on tissue regeneration in periodontitis: a multicenter randomized clinical trial","authors":"Yi Liu, Yitong Liu, Jingchao Hu, Jianhui Han, Lin Song, Xu Liu, Nannan Han, Xia Xia, Jia He, Hongfang Meng, Meng Wan, Haojie Wang, Xiaodan Liu, Zhanyi Gao, Xiao Wang, Chutse Wu, Songlin Wang","doi":"10.1038/s41392-025-02320-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02320-w","url":null,"abstract":"<p>Periodontitis causes the destruction of tooth-supporting tissues, and current therapies for periodontal regeneration are invasive. In this study, a human dental pulp stem cell (DPSC; hDP-MSC) injection was developed to promote periodontal regeneration through a non-invasive procedure. A total of 132 patients with chronic periodontitis (158 teeth) from two centers in China were included. Thirty-six were randomly assigned to different DPSC dose groups (ranging from 1 × 10⁶ to 1 × 10⁷ DPSCs per tooth, with nine injected with saline only), and 96 were randomly assigned to a single-injection group (1 × 10⁷/0.6 mL DPSCs), a double-injection group (1 × 10⁷/0.6 mL DPSCs × 2), or a saline group, in a 1:1:1 ratio. At 6 months post-therapy, attachment loss (AL), periodontal probing depth (PD), gingival recession (GR), tooth mobility (TM), and bone defect depth (BDD) were examined. The primary outcome was AL. DPSC injection resulted in greater improvement in BDD (0.30 ± 0.484 mm) compared to saline injection (0.04 ± 0.315 mm). Post hoc analysis showed that DPSC injection had significantly better outcomes in patients with stage III periodontitis (AL ≥ 5 mm): 54 patients received DPSCs, and 40 received saline. AL improved by 1.67 ± 1.508 mm in the DPSC group (26.81% improvement) and by 1.03 ± 1.310 mm in the saline group (17.43% improvement). The therapeutic effects encompassed improvements in both soft and hard tissues. In summary, DPSC injection was safe and improved clinical outcomes compared to saline injection in patients with stage III periodontitis. Larger trials are warranted to validate these findings (ClinicalTrials.gov registration: NCT05924373).</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"7 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747432","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":"Dynamics of neutralizing antibodies against COVID-19 Omicron subvariants following breakthrough infection in southwest China between December 2022 and April 2024","authors":"Yongquan He, Yi Yin, Yi Zhang, Huiping Yang, Zhiling Jiang, Fang Hao, Taiqiang Zhao, Xiaobin Liu, Yusong Liu, Yong Zeng, Xi Li, Xuemei Chen, Kaiju Xu, Chang Tan, Jie Yang, Li Jiang, Bo Gong, Zhenglin Yang","doi":"10.1038/s41392-025-02319-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02319-3","url":null,"abstract":"<p>From December 2022 to January 2023, the SARS-CoV-2 Omicron BA.5/BF.7 variant significantly impacted mainland China. While most COVID-19 patients experienced mild symptoms and were treated as outpatients or at home, some cases progressed to severe illness, necessitating hospitalization or even resulting in death. To better understand this outbreak and forecast future waves as SARS-CoV-2 continues to evolve, it is crucial to assess the titer of neutralizing antibodies (Nab) for evaluating the establishment of an immune barrier. In this study, we investigated the dynamic evolution of humoral immunity following the breakthrough infection wave driven by the SARS-CoV-2 Omicron BA.5/BF.7 variant in southwest China. Over a period of more than one year, we analyzed 3128 serum samples collected monthly to delineate the kinetics of Nab responses in a large cohort. Our data revealed a pronounced surge in Nab titers immediately after the December 2022–January 2023 outbreak, particularly among individuals primed with two or three doses of vaccine. As the epidemic progressed, emerging variants such as XBB.1.5, EG.5, and JN.1 elicited distinct immunological responses and demonstrated varying capacities for immune escape. Our findings underscore the rapid antigenic evolution of SARS-CoV-2 and the consequent challenges in sustaining effective population-level immunity, thereby advocating for continual surveillance and adaptive vaccine immunogen updates.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737170","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":"Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights","authors":"Lei Shi, Ziying Zhang, Song Mei, Zerui Wang, Zhe Xu, Weiqi Yao, Limin Liu, Mengqi Yuan, Yuefei Pan, Kaidi Zhu, Kai Liu, Fanglin Meng, Jiao Sun, Wenying Liu, Xiaohui Xie, Tengyun Dong, Lei Huang, Fanping Meng, Jun-Liang Fu, Yuanyuan Li, Chao Zhang, Xing Fan, Ming Shi, Yu Zhang, Yonggang Li, Wei-Fen Xie, Peng Zhang, Fu-Sheng Wang","doi":"10.1038/s41392-025-02318-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02318-4","url":null,"abstract":"<p>Decompensated liver cirrhosis (DLC) is characterized by severe liver dysfunction and immune dysregulation, posing significant treatment challenges. Mesenchymal stromal cell (MSC) therapy has shown promise in DLC treatment, but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear, limiting its clinical application. We conducted sequential Phase Ia/Ib trials using a single-arm, dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals. In Phase Ia, four dose cohorts received a single dose of MSCs: 5.0 × 10⁷, 1.0 × 10⁸, 1.5 × 10⁸, and 2.0 × 10⁸ cells. Patients were followed up on Days 3, 7, 14, and 28. Multiomics analyses, including single-cell RNA sequencing and cytometry by time of flight, were conducted to perform exploratory mechanistic analyses investigating immune cell dynamics and dose-dependent responses. Building on these findings, Phase Ib included two dose cohorts, each of which received three doses of MSCs administered one week apart: 1.0 × 10⁸ and 2.0 × 10⁸ cells per dose. Patients were followed up on Days 7, 14, 21, and 28 to further evaluate the safety and feasibility of multiple-dose regimens. The trials were registered at ClinicalTrials.gov (NCT05227846 and NCT05984303). MSC therapy demonstrated good safety and tolerability in both Phase Ia and Phase Ib trials, with no severe adverse events, dose-limiting toxicities, or serious unexpected adverse reactions observed up to Day 28. Multi-omics analyses revealed that higher MSC doses elicited stronger immunomodulatory effects, particularly by modulating monocyte subsets. In particular, myxovirus resistance 1 positive (MX1⁺) monocytes, a key monocyte population, exhibited dose-dependent changes and were identified as a mediator of MSC-induced immunomodulation. These effects were sustained for up to seven days post-treatment but diminished by Day 14. Preliminary clinical signals included improvements in Child–Pugh scores, Model for End-Stage Liver Disease scores, liver function markers, and quality-of-life metrics, particularly in the higher-dose and multiple-dose groups. This study demonstrates the safety and tolerability of MSC therapy in patients with DLC and provides the first human-based evidence on the dose‒effect relationship and optimal administration regimens. The identification of MX1⁺ monocytes as a critical mediator highlights the potential of MSC therapy to modulate immune dysfunction in DLC. These findings offer valuable insights for optimizing MSC therapy and informing the design of future efficacy-focused clinical trials.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"722 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719687","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":"Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions","authors":"Ping Jin, Xirui Duan, Zhao Huang, Yuan Dong, Jianmei Zhu, Huiming Guo, Hui Tian, Cheng-Gang Zou, Ke Xie","doi":"10.1038/s41392-025-02270-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02270-3","url":null,"abstract":"<p>Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate the expression of a wide range of target genes in response to endogenous and exogenous ligands, including steroid hormones, thyroid hormone, vitamin D, retinoic acid, fatty acids, and oxidative steroids. Upon ligand binding, nuclear receptors form dimer complexes with transcriptional cofactors, which interact with specific DNA sequences in the promoter or enhancer regions of target genes to modulate gene expression. This process plays a crucial role in many physiological processes such as reproduction, development, immune responses, metabolism, and homeostasis. Dysregulation of nuclear receptor signaling is implicated in the pathogenesis of numerous diseases, including cancers, metabolic disorders, cardiovascular diseases, and autoimmune conditions. Therefore, understanding the molecular mechanisms underlying nuclear receptor functions is essential for the development of novel therapeutic strategies. This review summarizes the current understanding of nuclear receptors in both physiological and pathological contexts, providing insights into the signaling pathways they regulate. Additionally, we discuss recent advances in drug development targeting nuclear receptors, with a focus on preclinical and clinical studies aimed at improving therapeutic efficacy. By exploring these therapeutic avenues, this article highlights the potential of nuclear receptors as promising targets for future treatments of a variety of human diseases, paving the way for more personalized and effective therapies in clinical medicine.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715283","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":"Astrocytic gamma-aminobutyric acid dysregulation as a therapeutic target for posttraumatic stress disorder","authors":"Sujung Yoon, Woojin Won, Suji Lee, Kayoung Han, Eunji Ha, Juheon Lee, Seung Jae Hyeon, Yoonji Joo, Haejin Hong, Hyangwon Lee, Yumi Song, Ki Duk Park, Bertrand R. Huber, Junghee Lee, Richard A. E. Edden, Minah Suh, Hoon Ryu, C. Justin Lee, In Kyoon Lyoo","doi":"10.1038/s41392-025-02317-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02317-5","url":null,"abstract":"<p>Post-traumatic stress disorder (PTSD) remains a debilitating psychiatric condition with limited pharmacological treatment options. Identifying novel therapeutic targets is critical for addressing its unmet clinical needs. Through our comprehensive human clinical research, including both cross-sectional and longitudinal studies, we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid (GABA) levels and PTSD symptoms. Notably, elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow (CBF) and symptom severity, normalizing with recovery, highlighting GABA dysregulation as a key mechanism in the disorder. Postmortem and PTSD-like mouse models implicated monoamine oxidase B (MAOB)-dependent astrocytic GABA as a primary driver of this imbalance, exacerbating deficit in fear extinction retrieval. Genetic and pharmacological inhibition of MAOB effectively restored astrocytic GABA and improved fear extinction retrieval in PTSD-like mouse models. Specifically, KDS2010, a recently developed highly selective and reversible MAOB inhibitor, not only restored astrocytic GABA homeostasis but also rescued CBF deficits and reduced tonic GABA and astrogliosis in the prefrontal cortex. Moreover, KDS2010 successfully advanced through Phase 1 clinical trials, showing a favorable safety profile and paving the way for Phase 2 trials to evaluate its therapeutic potential in PTSD. Our findings highlight the pivotal role of astrocytic GABA in PTSD pathophysiology and establish MAOB inhibition as a mechanistically targeted approach to alleviate symptoms. By bridging human and animal studies with translational clinical trials, this work positions KDS2010 as a promising first-in-class therapy, offering a novel paradigm for PTSD treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715316","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}