Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study's primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR+CD38+CD8+ T cell abundance serving as a potential predictor of therapeutic benefit.
由于支持转换疗法疗效的证据有限，转换疗法仍然是治疗不可切除肝细胞癌（uHCC）的一种不常见策略。为了解决这一差距，我们启动了一项前瞻性2期多中心试验（NCT04997850），比较lenvatinib联合lenvatinib、经动脉化疗栓塞（TACE）和PD-1抑制剂与单独TACE治疗肝癌患者的LEN-TAP方案。该研究的主要结局是挽救性肝切除（SLR）率；次要指标包括客观缓解率（ORR）、总生存期（OS）、无事件生存期（EFS）、无复发生存期（RFS）和安全性。从2020年10月到2021年11月，142名符合条件的参与者被分配到LEN-TAP （n = 71）或TACE单药治疗（n = 71）。在中位随访24.2个月时，LEN-TAP队列显示出更高的SLR率（59.2% vs. 18.3%, P < 0.001）和ORR （78.9% vs. 16.9%, P < 0.001）。LEN-TAP队列的中位OS、EFS和RFS也显著延长（未达到vs. 23.0个月，P < 0.001; 20.03 vs. 6.52个月，P < 0.001; 36.6 vs. 19.0个月，P = 0.048）。尽管LEN-TAP治疗相关的3级不良事件发生率更高（60.6% vs. 21.1%, P < 0.001），但未观察到4级或更高级别的毒性。通过单细胞测序和流式细胞术进行的探索性生物标志物评估将循环HLA-DR+CD38+CD8+ T细胞水平升高与改善的治疗反应联系起来。这些T细胞似乎通过CXCR6-PI3K-AKT信号轴潜在地介导抗肿瘤活性。总之，LEN-TAP方案显示出有希望的疗效和可接受的耐受性，作为uHCC的转化治疗，外周HLA-DR+CD38+CD8+ T细胞丰度可作为治疗获益的潜在预测因子。
{"title":"Lenvatinib plus transarterial chemoembolization and PD-1 inhibitors as conversion therapies for unresectable intermediate-advanced hepatocellular carcinoma: a phase 2 trial and exploratory biomolecular study.","authors":"Xiaoyun Zhang,Haozheng Cai,Wei Peng,Haiqing Wang,JiaYi Wu,Xinrui Zhu,Weixin Guo,Fei Xie,Yu Zhang,Ming Wang,Yu Yu,Yongjie Zhou,Chuan Li,Junyi Shen,Chang Liu,Yu Yang,Xiaozhong Jiang,Qiu Li,Weixia Chen,Yujun Shi,Wusheng Lu,Xin Sun,Xielin Feng,Maolin Yan,Shuqun Cheng,Tianfu Wen","doi":"10.1038/s41392-025-02498-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02498-z","url":null,"abstract":"Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study's primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR+CD38+CD8+ T cell abundance serving as a potential predictor of therapeutic benefit.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"17 1","pages":"37"},"PeriodicalIF":39.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014691","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":"Osimertinib inhibits the MYLK4-mediated phosphorylation of CDKAL1 to suppress stemness and chemoresistance in rhabdomyosarcoma.","authors":"Takuto Itano,Rongsheng Huang,Toshifumi Ozaki,Eiji Nakata,Atsushi Fujimura","doi":"10.1038/s41392-025-02548-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02548-6","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"258 1","pages":"26"},"PeriodicalIF":39.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014690","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}
Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene-environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework-integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization-to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = -0.038 to -0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = -22.1 mL/year per standardized unit; ECOPD: -0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber-related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.
{"title":"Multiomics Mendelian randomization identifies serpin family G member 1 as a chronic obstructive pulmonary disease modulator.","authors":"Erkang Yi,Jieda Cui,Hairong Wang,Fan Wu,Qiyang Hong,Qingyang Li,Chengshu Xie,Huahua Xu,Yu Liu,Xinru Ran,Xiaohui Wu,Qi Wan,Gaoying Tang,Leqing Zhu,Junling Pang,Yumin Zhou,Erping Long,Pixin Ran","doi":"10.1038/s41392-025-02547-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02547-7","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene-environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework-integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization-to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = -0.038 to -0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = -22.1 mL/year per standardized unit; ECOPD: -0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber-related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"36 1","pages":"34"},"PeriodicalIF":39.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005434","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}
Pub Date : 2026-01-20DOI: 10.1038/s41392-025-02546-8
Ugo Chianese, Chiara Papulino, Gerardo Saggese, Ahmad Ali, Marianna Ciotola, Enza Lonardo, Mirko Cortese, Gregorio Favale, Annabella Di Mauro, Danila La Gioia, Valentina Golino, Eduardo Sommella, Pietro Campiglia, Renato Franco, Fortunato Ciardiello, Ferdinando De Vita, Vincenzo Carafa, Lucia Altucci, Rosaria Benedetti
Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach-including metabolomics, proteomics, and lipidomics-was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.
{"title":"Glycolytic heterogeneity drives metabolic-targeted therapy in pancreatic ductal adenocarcinoma.","authors":"Ugo Chianese, Chiara Papulino, Gerardo Saggese, Ahmad Ali, Marianna Ciotola, Enza Lonardo, Mirko Cortese, Gregorio Favale, Annabella Di Mauro, Danila La Gioia, Valentina Golino, Eduardo Sommella, Pietro Campiglia, Renato Franco, Fortunato Ciardiello, Ferdinando De Vita, Vincenzo Carafa, Lucia Altucci, Rosaria Benedetti","doi":"10.1038/s41392-025-02546-8","DOIUrl":"10.1038/s41392-025-02546-8","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach-including metabolomics, proteomics, and lipidomics-was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":"25"},"PeriodicalIF":52.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12816621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003951","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}
Pub Date : 2026-01-19DOI: 10.1038/s41392-025-02401-w
Lijun Zhao,Jiamin Yuan,Qing Yang,Jing Ma,Fenghao Yang,Yutong Zou,Ke Liu,Fang Liu
Diabetic complications represent a formidable clinical challenge characterized by hyperglycemia-induced multiorgan dysfunction and dysregulated intercellular signaling networks. Advances in spatial multiomics and single-cell transcriptomic techniques, along with insights into aberrant signaling via myokines, cytokines, hormones, the gut microbiota, and exosomes, have revealed the molecular heterogeneity and dynamic inter-organ crosstalk underlying diabetes. Digital diabetes prevention programs have demonstrated effectiveness in high-risk populations through the use of remote tools to support lifestyle changes, reduce hemoglobin A1c, and delay the onset of type 2 diabetes. The therapeutic landscape for diabetic complications has been reshaped by agents with proven cardiorenal benefits, including sodium‒glucose cotransporter 2 inhibitors, glucagon‒like peptide-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, with combination therapies offering potential additive or synergistic effects. However, their optimal application requires careful benefit-risk assessment across diverse patient populations. Novel therapeutic strategies involving mesenchymal stem cells and their derived exosomes, gut microbiota modulation, bioactive compounds from traditional Chinese medicine, and AI-assisted disease management systems offer promising approaches to correct molecular dysfunctions. This review summarizes recent advances in the mechanisms, prevention, and treatment of diabetic complications, alongside a critical examination of current bottlenecks in translational applications. The remaining challenges include establishing long-term safe regenerative therapies and effectively integrating AI into clinical workflows. Although AI shows promise, issues such as limited data diversity and low model interpretability hinder its generalizability and clinical trust. Addressing these challenges will be essential for transitioning toward a proactive, personalized, and patient-centered model of care.
{"title":"Diabetes and its complications: molecular mechanisms, prevention and treatment.","authors":"Lijun Zhao,Jiamin Yuan,Qing Yang,Jing Ma,Fenghao Yang,Yutong Zou,Ke Liu,Fang Liu","doi":"10.1038/s41392-025-02401-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02401-w","url":null,"abstract":"Diabetic complications represent a formidable clinical challenge characterized by hyperglycemia-induced multiorgan dysfunction and dysregulated intercellular signaling networks. Advances in spatial multiomics and single-cell transcriptomic techniques, along with insights into aberrant signaling via myokines, cytokines, hormones, the gut microbiota, and exosomes, have revealed the molecular heterogeneity and dynamic inter-organ crosstalk underlying diabetes. Digital diabetes prevention programs have demonstrated effectiveness in high-risk populations through the use of remote tools to support lifestyle changes, reduce hemoglobin A1c, and delay the onset of type 2 diabetes. The therapeutic landscape for diabetic complications has been reshaped by agents with proven cardiorenal benefits, including sodium‒glucose cotransporter 2 inhibitors, glucagon‒like peptide-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, with combination therapies offering potential additive or synergistic effects. However, their optimal application requires careful benefit-risk assessment across diverse patient populations. Novel therapeutic strategies involving mesenchymal stem cells and their derived exosomes, gut microbiota modulation, bioactive compounds from traditional Chinese medicine, and AI-assisted disease management systems offer promising approaches to correct molecular dysfunctions. This review summarizes recent advances in the mechanisms, prevention, and treatment of diabetic complications, alongside a critical examination of current bottlenecks in translational applications. The remaining challenges include establishing long-term safe regenerative therapies and effectively integrating AI into clinical workflows. Although AI shows promise, issues such as limited data diversity and low model interpretability hinder its generalizability and clinical trust. Addressing these challenges will be essential for transitioning toward a proactive, personalized, and patient-centered model of care.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"269 1","pages":"22"},"PeriodicalIF":39.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994794","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}
Pub Date : 2026-01-19DOI: 10.1038/s41392-025-02545-9
Phuong Thi Thanh Nguyen,Ali Yousefian-Jazi,Seung Jae Hyeon,Soomin Lee,Seung Chan Kim,Uiyeol Park,Yeeun Jeong,Sojung Kim,Suhyun Kim,Yeyun Kim,Hannah L Ryu,Kyung Eun Lee,Thor D Stein,Richard H Myers,Eun Mi Hwang,Junghee Lee,Hoon Ryu
Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by a triad of behavioral symptoms: involuntary movement, emotional change, and cognitive dysfunction. Although alterations in WNT signaling have been reported in HD, its precise role in pathogenesis remains unclear. In this study, we found that astrocytic WNT5B mRNA and protein levels are elevated in the striatum of both HD patients and HD model mice. The noncanonical WNT5B signaling pathway induced sustained expression of matrix metallopeptidase 14 (MMP14), an extracellular matrix (ECM)-degrading enzyme, via activation of the NFATc2 transcription factor in both human and primary mouse astrocytes. Robust upregulation of MMP14 led to ECM degradation, medium spiny neuron (MSN) damage, and increased mutant huntingtin aggregation in N171-82Q HD transgenic mice. Furthermore, WNT5B gain-of-function exacerbated neuropathology, impaired motor coordination, and shortened the lifespan of N171-82Q mice. We further demonstrated that the overexpression of the estrogen receptor α (ERα) suppresses NFATc2 transcriptional activity in vitro. A targeted therapy for the WNT5B-NFATc2-MMP14 signaling pathway by genistein, a phytoestrogen, reduced MMP14 transcription by antagonizing NFATc2 activity and preventing ECM degradation in N171-82Q mice. Genistein treatment also ameliorated neuropathology and motor deficits and prolonged the lifespan of HD mice. Together, these findings define a molecular pathological mechanism in which astrocytic MMP14 transcription, driven by the noncanonical WNT5B signaling pathway, promotes ECM degradation and MSN damage and accelerates neurodegeneration in HD. Modulation of the noncell-autonomous WNT5B-NFATc2-MMP14 signaling pathway by genistein may serve as a potential therapeutic strategy for mitigating HD pathogenesis.
{"title":"Astrocytic noncanonical WNT5B signaling modulates extracellular matrix remodeling and neuropathology in Huntington's disease.","authors":"Phuong Thi Thanh Nguyen,Ali Yousefian-Jazi,Seung Jae Hyeon,Soomin Lee,Seung Chan Kim,Uiyeol Park,Yeeun Jeong,Sojung Kim,Suhyun Kim,Yeyun Kim,Hannah L Ryu,Kyung Eun Lee,Thor D Stein,Richard H Myers,Eun Mi Hwang,Junghee Lee,Hoon Ryu","doi":"10.1038/s41392-025-02545-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02545-9","url":null,"abstract":"Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by a triad of behavioral symptoms: involuntary movement, emotional change, and cognitive dysfunction. Although alterations in WNT signaling have been reported in HD, its precise role in pathogenesis remains unclear. In this study, we found that astrocytic WNT5B mRNA and protein levels are elevated in the striatum of both HD patients and HD model mice. The noncanonical WNT5B signaling pathway induced sustained expression of matrix metallopeptidase 14 (MMP14), an extracellular matrix (ECM)-degrading enzyme, via activation of the NFATc2 transcription factor in both human and primary mouse astrocytes. Robust upregulation of MMP14 led to ECM degradation, medium spiny neuron (MSN) damage, and increased mutant huntingtin aggregation in N171-82Q HD transgenic mice. Furthermore, WNT5B gain-of-function exacerbated neuropathology, impaired motor coordination, and shortened the lifespan of N171-82Q mice. We further demonstrated that the overexpression of the estrogen receptor α (ERα) suppresses NFATc2 transcriptional activity in vitro. A targeted therapy for the WNT5B-NFATc2-MMP14 signaling pathway by genistein, a phytoestrogen, reduced MMP14 transcription by antagonizing NFATc2 activity and preventing ECM degradation in N171-82Q mice. Genistein treatment also ameliorated neuropathology and motor deficits and prolonged the lifespan of HD mice. Together, these findings define a molecular pathological mechanism in which astrocytic MMP14 transcription, driven by the noncanonical WNT5B signaling pathway, promotes ECM degradation and MSN damage and accelerates neurodegeneration in HD. Modulation of the noncell-autonomous WNT5B-NFATc2-MMP14 signaling pathway by genistein may serve as a potential therapeutic strategy for mitigating HD pathogenesis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"38 1","pages":"23"},"PeriodicalIF":39.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994795","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}
Pub Date : 2026-01-17DOI: 10.1038/s41392-025-02552-w
Magdalena Wolska,Pilar Rodríguez-Viso,Anna Świątkowska,Edyta Bulanda,Tomasz P Wypych
{"title":"A microbiota-dependent bile acid reprograms alveolar macrophages to control lung inflammation.","authors":"Magdalena Wolska,Pilar Rodríguez-Viso,Anna Świątkowska,Edyta Bulanda,Tomasz P Wypych","doi":"10.1038/s41392-025-02552-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02552-w","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":"35"},"PeriodicalIF":39.3,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993026","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}
Although perioperative immunotherapy combined with neoadjuvant chemotherapy has improved the clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC), the optimal combination strategy remains unknown. This multicenter, open-label, randomized, phase II trial (ALTER-L043; NCT04846634) evaluated the efficacy and safety of perioperative penpulimab plus anlotinib with or without neoadjuvant chemotherapy in patients with resectable NSCLC. Eligible patients were randomly assigned (1:1:1) to receive 3-4 cycles of neoadjuvant penpulimab (200 mg on day 1) plus anlotinib (12 mg on days 1-14) and chemotherapy, penpulimab plus chemotherapy, or penpulimab plus anlotinib, followed by surgery and matching adjuvant therapy. The primary endpoint was the investigator-assessed major pathologic response (MPR) rate. Between December 3, 2021, and January 23, 2024, 90 patients were randomly assigned to the penpulimab plus anlotinib and chemotherapy (n = 30), penpulimab plus chemotherapy (n = 30), or penpulimab plus anlotinib (n = 30) groups. Definitive surgery was performed in 92.6%, 89.7%, and 70.0% of patients, respectively. Among those who underwent surgery, the MPR and pathological complete response rates were 76.0% (95% CI 54.9-90.6) and 52.0% (95% CI 31.3-72.2), respectively, in the penpulimab plus anlotinib and chemotherapy group; 57.7% (95% CI 36.9-76.7) and 50.0% (95% CI 29.9-70.1), respectively, in the penpulimab plus chemotherapy group; and 52.4% (95% CI 29.8-74.3) and 38.1% (95% CI 18.1-61.6), respectively, in the penpulimab plus anlotinib group. Across all treatment phases, the incidences of grade ≥3 treatment-related adverse events were 26.7%, 20.0%, and 30.0%, respectively. Penpulimab plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and a manageable safety profile in patients with resectable NSCLC, suggesting its potential as a viable perioperative treatment option.
尽管围手术期免疫治疗联合新辅助化疗改善了可切除非小细胞肺癌（NSCLC）患者的临床预后，但最佳联合策略仍不清楚。这项多中心、开放标签、随机、II期试验（alt - l043; NCT04846634）评估了可切除的非小细胞肺癌患者围手术期penpulimab + anlotinib联合或不联合新辅助化疗的有效性和安全性。符合条件的患者被随机分配（1:1:1）接受3-4个周期的新辅助彭普利单抗（第1天200 mg） +安洛替尼（第1-14天12 mg）和化疗，彭普利单抗+化疗，或彭普利单抗+安洛替尼，随后进行手术和匹配的辅助治疗。主要终点是研究者评估的主要病理反应（MPR）率。在2021年12月3日至2024年1月23日期间，90名患者被随机分配到penpulimab + anlotinib +化疗组（n = 30）、penpulimab +化疗组（n = 30）或penpulimab + anlotinib组（n = 30）。最终手术率分别为92.6%、89.7%和70.0%。在接受手术的患者中，泮普利单抗+安洛替尼+化疗组的MPR和病理完全缓解率分别为76.0% （95% CI 54.9-90.6）和52.0% (95% CI 31.3-72.2)；彭普利单抗加化疗组分别为57.7% （95% CI 36.9-76.7）和50.0% (95% CI 29.9-70.1)；彭普利单抗加安洛替尼组分别为52.4% （95% CI 29.8-74.3）和38.1% （95% CI 18.1-61.6）。在所有治疗阶段，≥3级治疗相关不良事件的发生率分别为26.7%、20.0%和30.0%。在可切除的非小细胞肺癌患者中，Penpulimab + anlotinib联合或不联合新辅助化疗显示出良好的疗效和可控的安全性，这表明它有可能成为一种可行的围手术期治疗选择。
{"title":"Perioperative penpulimab-based combination therapy in patients with resectable non-small cell lung cancer (ALTER-L043): an open-label, multicenter, randomized, phase II trial.","authors":"Meng Wang,Weiran Liu,Hongbo Guo,Hao Long,Bentong Yu,Guofang Zhao,Jun Wu,Dongsheng Yue,Xiaoliang Zhao,Chenguang Li,Lianmin Zhang,Shengguang Wang,Qiang Zhang,Zhenfa Zhang,Changli Wang","doi":"10.1038/s41392-025-02544-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02544-w","url":null,"abstract":"Although perioperative immunotherapy combined with neoadjuvant chemotherapy has improved the clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC), the optimal combination strategy remains unknown. This multicenter, open-label, randomized, phase II trial (ALTER-L043; NCT04846634) evaluated the efficacy and safety of perioperative penpulimab plus anlotinib with or without neoadjuvant chemotherapy in patients with resectable NSCLC. Eligible patients were randomly assigned (1:1:1) to receive 3-4 cycles of neoadjuvant penpulimab (200 mg on day 1) plus anlotinib (12 mg on days 1-14) and chemotherapy, penpulimab plus chemotherapy, or penpulimab plus anlotinib, followed by surgery and matching adjuvant therapy. The primary endpoint was the investigator-assessed major pathologic response (MPR) rate. Between December 3, 2021, and January 23, 2024, 90 patients were randomly assigned to the penpulimab plus anlotinib and chemotherapy (n = 30), penpulimab plus chemotherapy (n = 30), or penpulimab plus anlotinib (n = 30) groups. Definitive surgery was performed in 92.6%, 89.7%, and 70.0% of patients, respectively. Among those who underwent surgery, the MPR and pathological complete response rates were 76.0% (95% CI 54.9-90.6) and 52.0% (95% CI 31.3-72.2), respectively, in the penpulimab plus anlotinib and chemotherapy group; 57.7% (95% CI 36.9-76.7) and 50.0% (95% CI 29.9-70.1), respectively, in the penpulimab plus chemotherapy group; and 52.4% (95% CI 29.8-74.3) and 38.1% (95% CI 18.1-61.6), respectively, in the penpulimab plus anlotinib group. Across all treatment phases, the incidences of grade ≥3 treatment-related adverse events were 26.7%, 20.0%, and 30.0%, respectively. Penpulimab plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and a manageable safety profile in patients with resectable NSCLC, suggesting its potential as a viable perioperative treatment option.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"52 1","pages":"21"},"PeriodicalIF":39.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986329","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}
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