SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi-Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.
{"title":"Selective depletion of tumor-associated SAMHD1 enhances chemotherapeutic efficacy and antitumor immune responses.","authors":"Jing Sun,Wenwen Zheng,Zheng-Guo Zhang,Hongkun Zhou,Songdi Wang,Dingbo Huang,Xiao-Yi Hu,Qing-Feng Yu,Zhao-Xing Wu,Yi-Fei Shi,Runxin Ye,Fengyan Xia,Wangwei Li,Shurui Lyu,Yu Huang,Xu-Zhao Zhang,Fei Xu,Ke Zhao,Jie Yang,Juan Du,Jiaming Su,Yajuan Rui,Rongzhen Xu,Wei-Ming Yang,Cang Li,Jia Ling Xu,Ruiyu Zhu,Xiaoguang Wang,Wei Wei,Xiao-Fang Yu","doi":"10.1038/s41392-025-02523-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02523-1","url":null,"abstract":"SAMHD1 is a human deoxyribonucleoside triphosphatase (dNTPase) known for its role as a restriction factor that targets a wide spectrum of viruses, its involvement in autoimmune disease Aicardi-Goutières syndrome (AGS), and its participation in innate immune regulation. The role of SAMHD1 in cancer, particularly its contribution to drug resistance, has gained increasing attention in recent years. One significant scientific challenge is how to inhibit SAMHD1 function in tumor cells while preserving its function in normal primary cells. Herein, we identified that increased SAMHD1 expression levels correlate with poor prognosis across multiple cancer types, and that SAMHD1 is upregulated in a variety of tumors. Through proteomic analysis and drug screening, we identified a promising strategy for selectively depleting tumor-associated SAMHD1 while minimizing its impact on SAMHD1 expression in key normal cell types. Our approach effectively enhanced tumor cytotoxicity when combined with multiple chemotherapeutic agents and suppressed tumor growth in vivo. Moreover, selective depletion of tumor-associated SAMHD1 activated innate immune responses, leading to enhanced tumor cell killing by immune cells. Collectively, these findings suggest that targeting tumor-specific SAMHD1 represents a novel and promising therapeutic strategy for cancers characterized by elevated SAMHD1 expression, offering potential for improved treatment outcomes in cancer patients with high SAMHD1 expression.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"4 1","pages":"406"},"PeriodicalIF":39.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752521","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}
To assess the efficacy and safety of L-oxiracetam, a novel nootropic agent, in improving cognition in patients with TBI, we performed a multicentre, double-blind, randomized controlled trial in China. Participants aged 18 to 75 years with TBI (Glasgow Coma Scale score of 10 to 15) were recruited from 51 hospitals from 2019 to 2024. Patients were randomly assigned to L-oxiracetam, 4 g/day, oxiracetam 6 g/day, or placebo in 2:2:1. The primary outcome was the change in the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score from baseline to 90 days post treatment. Secondary outcomes included changes in additional cognitive evaluations, neurological function, activities of daily living (ADL), and adverse events (AEs). The trial was approved by the China National Medical Products Administration (2016L03521), and registered at Clinicaltrials.gov (NCT04205565) and Chinadrugtrials.org.cn (CTR20192539). Five hundred and ninety patients were included (mean age (SD), 50.9 (14.5); 421 males). The least squares (LS) mean of LOTCA change from baseline to 90 days post treatment was 20.45 (95% confidence interval [CI] 17.23, 23.66) in the L-oxiracetam group, 15.90 (95% CI 12.71, 19.10) in the oxiracetam group, and 11.47 (95% CI 7.75, 15.20) in the placebo group (P value < 0.05 for all groups). The LS mean difference of the L-oxiracetam was significantly higher than the placebo group (8.97, 95% CI 5.69,12.26; P < 0.001; Cohen's d = 0.48 [95% CI: 0.26,0.69]) and the oxiracetam group (4.54, 95% CI 1.85,7.23). Secondary efficacy outcomes did not differ between the L-oxiracetam and oxiracetam groups. The proportion of serious AEs did not differ among the three groups. L-oxiracetam could improve cognitive function in patients with mild-to-moderate TBI. L-oxiracetam might be more efficacious than oxiracetam. No significant safety concerns were reported. Despite limitations such as loss to follow-up, the findings of this study provide important evidence for the clinical management of cognitive dysfunction following TBI. Future studies in real-world clinical settings are warranted to further substantiate the efficacy of L-oxiracetam and oxiracetam.
为了评估l -奥拉西坦（一种新型益智药物）改善TBI患者认知能力的有效性和安全性，我们在中国进行了一项多中心、双盲、随机对照试验。2019年至2024年从51家医院招募年龄在18至75岁之间的TBI患者（格拉斯哥昏迷评分为10至15）。患者按2:2:1的比例随机分配到l -奥拉西坦组，4 g/天，6 g/天，或安慰剂组。主要结果是Loewenstein职业治疗认知评估（LOTCA）评分从基线到治疗后90天的变化。次要结局包括额外认知评估、神经功能、日常生活活动（ADL）和不良事件（ae）的变化。该试验已获得中国国家药品监督管理局批准（2016L03521），并在Clinicaltrials.gov （NCT04205565）和chinadrutrials.org.cn （CTR20192539）上注册。纳入590例患者(平均年龄（SD）， 50.9岁（14.5岁）；421男性)。治疗后90天，l -奥拉西坦组LOTCA变化的最小二乘（LS）平均值为20.45(95%可信区间[CI] 17.23, 23.66)，奥拉西坦组为15.90 (95% CI 12.71, 19.10)，安慰剂组为11.47 (95% CI 7.75, 15.20)（各组P值均< 0.05）。l -奥拉西坦的LS平均差异显著高于安慰剂组（8.97,95% CI 5.69,12.26; P < 0.001; Cohen’s d = 0.48 [95% CI: 0.26,0.69]）和奥拉西坦组（4.54,95% CI 1.85,7.23）。l -奥拉西坦组和奥拉西坦组的次要疗效结果没有差异。三组患者发生严重不良反应的比例无显著差异。l -奥拉西坦可改善轻中度TBI患者的认知功能。左旋奥拉西坦可能比奥拉西坦更有效。没有重大的安全隐患报告。尽管缺乏随访等局限性，但本研究结果为TBI后认知功能障碍的临床治疗提供了重要证据。未来的临床研究将进一步证实l-奥拉西坦和奥拉西坦的疗效。
{"title":"Efficacy and safety of L-oxiracetam on cognitive function in patients with traumatic brain injury: a multicentre, randomised, double-blind, phase 3 clinical trial.","authors":"Tao Liu,Jiao Wang,Zhihao Zhao,Weiwei Jiang,Minzhi Zhang,Yunhu Yu,Yang Liu,Mingqi Liu,Linan Chen,Hengzhu Zhang,Yingbiao Hong,Bohe Li,Rutong Yu,Hongming Ji,Liang Mi,Biao Zhao,Chuanxiang Lv,Chenglong Liu,Jianning Zhang,Rongcai Jiang, ","doi":"10.1038/s41392-025-02492-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02492-5","url":null,"abstract":"To assess the efficacy and safety of L-oxiracetam, a novel nootropic agent, in improving cognition in patients with TBI, we performed a multicentre, double-blind, randomized controlled trial in China. Participants aged 18 to 75 years with TBI (Glasgow Coma Scale score of 10 to 15) were recruited from 51 hospitals from 2019 to 2024. Patients were randomly assigned to L-oxiracetam, 4 g/day, oxiracetam 6 g/day, or placebo in 2:2:1. The primary outcome was the change in the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) score from baseline to 90 days post treatment. Secondary outcomes included changes in additional cognitive evaluations, neurological function, activities of daily living (ADL), and adverse events (AEs). The trial was approved by the China National Medical Products Administration (2016L03521), and registered at Clinicaltrials.gov (NCT04205565) and Chinadrugtrials.org.cn (CTR20192539). Five hundred and ninety patients were included (mean age (SD), 50.9 (14.5); 421 males). The least squares (LS) mean of LOTCA change from baseline to 90 days post treatment was 20.45 (95% confidence interval [CI] 17.23, 23.66) in the L-oxiracetam group, 15.90 (95% CI 12.71, 19.10) in the oxiracetam group, and 11.47 (95% CI 7.75, 15.20) in the placebo group (P value < 0.05 for all groups). The LS mean difference of the L-oxiracetam was significantly higher than the placebo group (8.97, 95% CI 5.69,12.26; P < 0.001; Cohen's d = 0.48 [95% CI: 0.26,0.69]) and the oxiracetam group (4.54, 95% CI 1.85,7.23). Secondary efficacy outcomes did not differ between the L-oxiracetam and oxiracetam groups. The proportion of serious AEs did not differ among the three groups. L-oxiracetam could improve cognitive function in patients with mild-to-moderate TBI. L-oxiracetam might be more efficacious than oxiracetam. No significant safety concerns were reported. Despite limitations such as loss to follow-up, the findings of this study provide important evidence for the clinical management of cognitive dysfunction following TBI. Future studies in real-world clinical settings are warranted to further substantiate the efficacy of L-oxiracetam and oxiracetam.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"20 1","pages":"401"},"PeriodicalIF":39.3,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728423","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 : 2025-12-11DOI: 10.1038/s41392-025-02491-6
Michael Rassner,Tony Andreas Müller,Kirstyn Anne Crossley,Geoffroy Andrieux,Sabina Schaberg,Cornelia Endres,Lena Jakob,Teresa Poggio,Natalie Köhler,Julia Kolter,Gerhard Müller-Newen,Katharina Schönberger,Nina Cabezas-Wallscheid,Irene Gonzalez-Menendez,Leticia Quintanilla-Martinez,Melissa Zwick,Driti Ashok,Tanja Nicole Hartmann,Olaf Groß,Oliver Gorka,Marie Follo,Anna Lena Illert,Melanie Boerries,Robert Zeiser,Justus Duyster
Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6-JAK-STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.
{"title":"Oncostatin M induced by STAT5-activating oncogenes promotes disease progression in hematologic malignancies.","authors":"Michael Rassner,Tony Andreas Müller,Kirstyn Anne Crossley,Geoffroy Andrieux,Sabina Schaberg,Cornelia Endres,Lena Jakob,Teresa Poggio,Natalie Köhler,Julia Kolter,Gerhard Müller-Newen,Katharina Schönberger,Nina Cabezas-Wallscheid,Irene Gonzalez-Menendez,Leticia Quintanilla-Martinez,Melissa Zwick,Driti Ashok,Tanja Nicole Hartmann,Olaf Groß,Oliver Gorka,Marie Follo,Anna Lena Illert,Melanie Boerries,Robert Zeiser,Justus Duyster","doi":"10.1038/s41392-025-02491-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02491-6","url":null,"abstract":"Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6-JAK-STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":"400"},"PeriodicalIF":39.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717881","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}
Hyperuricemia is considered a modifiable risk factor for the development and progression of chronic kidney disease (CKD). There remains controversy over the effects of urate-lowering therapy (ULT) on kidney outcomes in patients with CKD and hyperuricemia. We conducted a cohort study using a sequential target trial emulation framework to evaluate the composite kidney outcomes in patients with CKD and hyperuricemia initiating ULT versus supportive care alone (control). A total of 269,831 eligible person trials (56,936 unique persons) with CKD and hyperuricemia who had received supportive care were included from the China Renal Data System database. The primary outcome was a composite kidney outcome defined as a greater than 40% decline in the estimated GFR or end-stage kidney disease (ESKD). The 3-year cumulative incidence rates of the composite kidney outcomes were 19.69% and 23.22% in the ULT group and the control group, respectively, with a risk difference of -3.53% (95% CI, -5.25% to -1.94%). The estimated 3-year risk differences for ESKD, all-cause mortality, and cardiovascular mortality were -1.88% (-3.28% to -0.45%), -2.25% (-3.02% to -1.51%), and -0.69% (-1.33% to -0.05%), respectively, all of which favor the ULT group. The estimates from the subgroup and sensitivity analyses were consistent with those from the primary analysis. Thus, ULT is associated with a significantly lower risk of kidney disease progression and mortality in patients with stage 3 or higher CKD and hyperuricemia. Large randomized clinical trials with refined designs are needed to assess the effect of ULT in these patients.
{"title":"Urate-lowering therapy and kidney outcomes in patients with chronic kidney disease and hyperuricemia.","authors":"Sheng Nie,Shiyu Zhou,Ruixuan Chen,Lantian Li,Yinfang Sun,Jiao Liu,Luhua Jin,Xian Shao,Mingzhen Pang,Licong Su,Fan Luo,Xin Xu,Fan Fan Hou","doi":"10.1038/s41392-025-02497-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02497-0","url":null,"abstract":"Hyperuricemia is considered a modifiable risk factor for the development and progression of chronic kidney disease (CKD). There remains controversy over the effects of urate-lowering therapy (ULT) on kidney outcomes in patients with CKD and hyperuricemia. We conducted a cohort study using a sequential target trial emulation framework to evaluate the composite kidney outcomes in patients with CKD and hyperuricemia initiating ULT versus supportive care alone (control). A total of 269,831 eligible person trials (56,936 unique persons) with CKD and hyperuricemia who had received supportive care were included from the China Renal Data System database. The primary outcome was a composite kidney outcome defined as a greater than 40% decline in the estimated GFR or end-stage kidney disease (ESKD). The 3-year cumulative incidence rates of the composite kidney outcomes were 19.69% and 23.22% in the ULT group and the control group, respectively, with a risk difference of -3.53% (95% CI, -5.25% to -1.94%). The estimated 3-year risk differences for ESKD, all-cause mortality, and cardiovascular mortality were -1.88% (-3.28% to -0.45%), -2.25% (-3.02% to -1.51%), and -0.69% (-1.33% to -0.05%), respectively, all of which favor the ULT group. The estimates from the subgroup and sensitivity analyses were consistent with those from the primary analysis. Thus, ULT is associated with a significantly lower risk of kidney disease progression and mortality in patients with stage 3 or higher CKD and hyperuricemia. Large randomized clinical trials with refined designs are needed to assess the effect of ULT in these patients.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"26 1","pages":"399"},"PeriodicalIF":39.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704641","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}
Clear cell renal cell carcinoma (ccRCC) is characterized by profound lipid metabolic dysregulation, yet the mechanisms linking peritumoral adipose tissue (PAT)-derived lipid metabolites to tumor aggressiveness remain poorly defined. Here, we identified lysophosphatidylethanolamine 18:1 (LPE18:1), a lipid metabolite enriched in PAT and the arterial blood of ccRCC patients, as a critical driver of tumor growth and lipid deposition. Through multiomics analyses and functional studies, we demonstrated that LPE18:1 upregulates F-actin-capping protein subunit alpha-1 (CAPZA1), which recruits ubiquitin-specific peptidase 48 (USP48) to stabilize the NAD-dependent protein deacetylase sirtuin-6 (SIRT6) by inhibiting its proteasomal degradation. Increased SIRT6 epigenetically promotes acetyl-CoA acetyltransferase 2 (ACAT2) expression, redirecting lipid metabolism toward free cholesterol accumulation-a hallmark of ccRCC aggressiveness. Clinically, CAPZA1 and SIRT6 levels correlate with advanced tumor stage and poor prognosis in ccRCC cohorts. Genetic or pharmacological inhibition of the CAPZA1/SIRT6 axis can reverse LPE18:1-induced lipid deposition and tumor progression in xenograft models. Notably, targeting this axis with the SIRT6 inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.
{"title":"Lysophosphatidylethanolamine 18:1 drives clear cell renal cell carcinoma by stabilizing SIRT6 to reprogram lipid metabolism.","authors":"Nanxi Yue,Hongye Zhao,Yong Zhang,Junfei Gu,Jinchun Qi,Jinkun Wen,Wei Wang,Mingming Lv,Hao Sun,Jinsuo Chen,Chenxiao Yang,Changbao Qu,Xiaonan Chen,Zhan Yang","doi":"10.1038/s41392-025-02496-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02496-1","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is characterized by profound lipid metabolic dysregulation, yet the mechanisms linking peritumoral adipose tissue (PAT)-derived lipid metabolites to tumor aggressiveness remain poorly defined. Here, we identified lysophosphatidylethanolamine 18:1 (LPE18:1), a lipid metabolite enriched in PAT and the arterial blood of ccRCC patients, as a critical driver of tumor growth and lipid deposition. Through multiomics analyses and functional studies, we demonstrated that LPE18:1 upregulates F-actin-capping protein subunit alpha-1 (CAPZA1), which recruits ubiquitin-specific peptidase 48 (USP48) to stabilize the NAD-dependent protein deacetylase sirtuin-6 (SIRT6) by inhibiting its proteasomal degradation. Increased SIRT6 epigenetically promotes acetyl-CoA acetyltransferase 2 (ACAT2) expression, redirecting lipid metabolism toward free cholesterol accumulation-a hallmark of ccRCC aggressiveness. Clinically, CAPZA1 and SIRT6 levels correlate with advanced tumor stage and poor prognosis in ccRCC cohorts. Genetic or pharmacological inhibition of the CAPZA1/SIRT6 axis can reverse LPE18:1-induced lipid deposition and tumor progression in xenograft models. Notably, targeting this axis with the SIRT6 inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"398"},"PeriodicalIF":39.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696639","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}
The nuclear receptor 4A1(NR4A1) plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes; however, its functional role and pharmacological potential in mesangial proliferative glomerulonephritis (MsPGN) remain unexplored. In this study, we found that downregulation of NR4A1 promotes the pathogenesis of MsPGN by regulating inflammatory and proliferative responses in mesangial cells (MCs), whereas overexpression of NR4A1 reverses these processes. Bruceine A (BA) binds to NR4A1 at residues D481/Q568 and exhibits NR4A1-dependent anti-inflammatory and anti-proliferative effects both in vitro and in vivo. Notably, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of NR4A1 alleviates glomerular injury and inflammatory cascades, while knockout of NR4A1 impairs the renoprotective effects of BA. BA binds to the ligand-binding domain (LBD) of NR4A1 and further sterically blocks K48-linked polyubiquitination at K558, thereby stabilizing NR4A1 protein levels. This stabilization enables NR4A1 to auto-activate its own promoter, amplifying the transcriptional repression of nuclear factor kappa-B (NF-κB) signaling phosphorylation, which ultimately attenuates inflammatory cascades and mesangial proliferation to confer renal protection. This study provides a promising therapeutic avenue for the development of next-generation therapies against MsPGN.
核受体4A1（NR4A1）在维持细胞内稳态中起着至关重要的作用，并参与各种疾病过程；然而，其在系膜增生性肾小球肾炎（MsPGN）中的功能作用和药理潜力仍未被探索。在这项研究中，我们发现NR4A1的下调通过调节系膜细胞（MCs）的炎症和增殖反应来促进MsPGN的发病机制，而NR4A1的过表达则逆转这些过程。Bruceine A （BA）在D481/Q568位点与NR4A1结合，在体外和体内均表现出NR4A1依赖的抗炎和抗增殖作用。值得注意的是，腺相关病毒血清型9 （AAV9）介导的NR4A1过表达减轻了肾小球损伤和炎症级联反应，而敲除NR4A1则削弱了BA的肾保护作用。BA结合NR4A1的配体结合域（LBD），进一步在K558位点立体阻断k48连接的多泛素化，从而稳定NR4A1蛋白水平。这种稳定性使NR4A1能够自动激活其自身的启动子，放大对核因子κ b （NF-κB）信号磷酸化的转录抑制，最终减轻炎症级联反应和肾系膜增殖，从而赋予肾脏保护作用。该研究为开发下一代治疗MsPGN的方法提供了一条有希望的治疗途径。
{"title":"Bruceine A protects nuclear receptor 4A1 from ubiquitin-degradation to alleviate mesangial proliferative glomerulonephritis.","authors":"Huating Hu,Runze Li,Kancheng He,Lingling Wu,Rongrong Li,Jiayan Lu,Ruimin Tian,Chuanghai Zhang,Jiayan He,Yulian Chen,Ruogu Lai,Jiaqi Zhang,Jiaqi Wu,Ying Zheng,Jinlian He,Liang Liu,Xiangmei Chen,Hudan Pan","doi":"10.1038/s41392-025-02495-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02495-2","url":null,"abstract":"The nuclear receptor 4A1(NR4A1) plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes; however, its functional role and pharmacological potential in mesangial proliferative glomerulonephritis (MsPGN) remain unexplored. In this study, we found that downregulation of NR4A1 promotes the pathogenesis of MsPGN by regulating inflammatory and proliferative responses in mesangial cells (MCs), whereas overexpression of NR4A1 reverses these processes. Bruceine A (BA) binds to NR4A1 at residues D481/Q568 and exhibits NR4A1-dependent anti-inflammatory and anti-proliferative effects both in vitro and in vivo. Notably, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of NR4A1 alleviates glomerular injury and inflammatory cascades, while knockout of NR4A1 impairs the renoprotective effects of BA. BA binds to the ligand-binding domain (LBD) of NR4A1 and further sterically blocks K48-linked polyubiquitination at K558, thereby stabilizing NR4A1 protein levels. This stabilization enables NR4A1 to auto-activate its own promoter, amplifying the transcriptional repression of nuclear factor kappa-B (NF-κB) signaling phosphorylation, which ultimately attenuates inflammatory cascades and mesangial proliferation to confer renal protection. This study provides a promising therapeutic avenue for the development of next-generation therapies against MsPGN.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"203 1","pages":"397"},"PeriodicalIF":39.3,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673898","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}
The widespread clinical application of paclitaxel (PTX) in cancer treatment has been significantly limited by the emergence of drug resistance and the presence of drug-tolerant persister cells. To systematically identify key regulators of this resistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which revealed that cell division cycle 6 (CDC6) is a critical determinant of cell adhesion-mediated PTX resistance. Furthermore, our results illustrate that CDC6, an essential DNA replication licensing factor, functions through a pathway distinct from previously well-characterized resistance mechanisms. Genetic depletion of CDC6 considerably sensitizes cells, markedly increasing PTX-induced cell death. In addition to its established role in chromosome stability, CDC6 physically interacts with tropomodulin-3 (Tmod3) in the cytoplasmic compartment. This interaction enhances CDC6 protein stability and drives drug resistance phenotypes through the regulation of actin cytoskeleton remodeling and facilitating focal adhesion assembly. In addition, combination treatment with PTX and actin filament inhibitors synergistically enhanced the antitumor efficacy both in vitro and in vivo. Overall, our studies elucidate the mechanisms through which CDC6 functions as a key regulator of PTX resistance and provide a potential therapeutic strategy to increase PTX efficacy through the modulation of the cytoskeletal-adhesion axis.
{"title":"Interaction between CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly.","authors":"Yue Liu,Huirui Wang,Jie Zhan,Jiabo Sun,Yan Sun,Xiaojie Fu,Dongxue Lv,Xiuyun Li,Ting Dong,Hongxiang Lou","doi":"10.1038/s41392-025-02490-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02490-7","url":null,"abstract":"The widespread clinical application of paclitaxel (PTX) in cancer treatment has been significantly limited by the emergence of drug resistance and the presence of drug-tolerant persister cells. To systematically identify key regulators of this resistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which revealed that cell division cycle 6 (CDC6) is a critical determinant of cell adhesion-mediated PTX resistance. Furthermore, our results illustrate that CDC6, an essential DNA replication licensing factor, functions through a pathway distinct from previously well-characterized resistance mechanisms. Genetic depletion of CDC6 considerably sensitizes cells, markedly increasing PTX-induced cell death. In addition to its established role in chromosome stability, CDC6 physically interacts with tropomodulin-3 (Tmod3) in the cytoplasmic compartment. This interaction enhances CDC6 protein stability and drives drug resistance phenotypes through the regulation of actin cytoskeleton remodeling and facilitating focal adhesion assembly. In addition, combination treatment with PTX and actin filament inhibitors synergistically enhanced the antitumor efficacy both in vitro and in vivo. Overall, our studies elucidate the mechanisms through which CDC6 functions as a key regulator of PTX resistance and provide a potential therapeutic strategy to increase PTX efficacy through the modulation of the cytoskeletal-adhesion axis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"113 1","pages":"395"},"PeriodicalIF":39.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664327","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 inflammation in adipose tissue is widely recognized as a pivotal link connecting obesity to a spectrum of related chronic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disorders. In this pathogenic process, the dysregulated interaction between adipocytes and adipose-resident immune cells plays a critical regulatory role; however, the underlying mechanisms governing this abnormal interaction remain largely unknown. In this study, we showed that upregulated β2-microglobulin expression in hypertrophic adipocytes during obesity not only mediated the activation of adipose-resident CD8+ T cells in a cell contact-dependent manner but also facilitated iron overload and the ferroptosis of adipocytes, thereby promoting the M1 polarization of adipose tissue macrophages. Conversely, specific ablation of β2-microglobulin in adipocytes effectively suppressed the activation and accumulation of adipose-resident CD8+ T cells, as well as adipocyte ferroptosis and M1 polarization, ultimately preventing high-fat diet-induced obesity and its related inflammation and metabolic disorders. Additionally, adeno-associated virus-mediated adipose-targeted knockdown of β2-microglobulin has been demonstrated to therapeutically alleviate high-fat diet-induced obesity, as well as its related chronic inflammation and metabolic disorders. Furthermore, our bioinformatic analysis of human adipose transcriptome data revealed a strong correlation between adipose β2-microglobulin and obesity. More importantly, β2-microglobulin is significantly upregulated in adipocytes isolated from patients with obesity. Thus, our findings highlight the pivotal role of adipocytes in obesity-associated chronic inflammation and metabolic disorders via β2-microglobulin-dependent mechanisms.
{"title":"Adipocytes orchestrate obesity-related chronic inflammation through β2-microglobulin.","authors":"Jie Li,Yuhao Li,Xiaoyang Zhou,Shushu Yang,Dong Liu,Hao Wen,Xiaoling Chen,Chengjie Duan,Meiling Yu,Mengjun Zhang,Bo Tang,Yong Wang,Li Wang,Yuzhang Wu","doi":"10.1038/s41392-025-02486-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02486-3","url":null,"abstract":"Chronic inflammation in adipose tissue is widely recognized as a pivotal link connecting obesity to a spectrum of related chronic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disorders. In this pathogenic process, the dysregulated interaction between adipocytes and adipose-resident immune cells plays a critical regulatory role; however, the underlying mechanisms governing this abnormal interaction remain largely unknown. In this study, we showed that upregulated β2-microglobulin expression in hypertrophic adipocytes during obesity not only mediated the activation of adipose-resident CD8+ T cells in a cell contact-dependent manner but also facilitated iron overload and the ferroptosis of adipocytes, thereby promoting the M1 polarization of adipose tissue macrophages. Conversely, specific ablation of β2-microglobulin in adipocytes effectively suppressed the activation and accumulation of adipose-resident CD8+ T cells, as well as adipocyte ferroptosis and M1 polarization, ultimately preventing high-fat diet-induced obesity and its related inflammation and metabolic disorders. Additionally, adeno-associated virus-mediated adipose-targeted knockdown of β2-microglobulin has been demonstrated to therapeutically alleviate high-fat diet-induced obesity, as well as its related chronic inflammation and metabolic disorders. Furthermore, our bioinformatic analysis of human adipose transcriptome data revealed a strong correlation between adipose β2-microglobulin and obesity. More importantly, β2-microglobulin is significantly upregulated in adipocytes isolated from patients with obesity. Thus, our findings highlight the pivotal role of adipocytes in obesity-associated chronic inflammation and metabolic disorders via β2-microglobulin-dependent mechanisms.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"55 1","pages":"394"},"PeriodicalIF":39.3,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657015","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}
Osimertinib, the first approved third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), exhibits notable efficacy in EGFR-mutant non-small cell lung cancer (NSCLC). This is a prospective, multicenter, comprehensive genomic profile signature (GPS) study in paired tissue and plasma samples from 149 patients with advanced NSCLC harboring EGFR exon 19 deletion (Ex19del) or L858R mutation at the first-line treatment failure of osimertinib (NCT05219162). Next-generation sequencing (NGS) was used for comprehensive GPS analysis of paired tissue and plasma samples. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used for tissue samples, while droplet digital polymerase chain reaction (ddPCR) and NGS were used for plasma samples to perform a concordance analysis of MET amplification. At the first-line treatment failure of osimertinib (study entry), EGFR alterations in tissue samples included EGFR Ex19del (49.0%, 73/149), EGFR L858R mutation (43.0%, 64/149), EGFR amplification (32.9%, 49/149), EGFR L718Q/V mutation (4.7%, 7/149), and EGFR C797S mutation (3.4%, 5/149); bypass signaling activation and downstream pathway activation alterations included TP53 mutation (69.8%, 104/149) and MET amplification (30.9%, 46/149). Among the 136 patients with EGFR Ex19del/L858R mutation in tissue samples, 72.1% (98/136), 35.3% (48/136), and 32.4% (44/136) had TP53 mutations, EGFR amplification, and MET amplification, respectively. Taking tissue samples as references, the GPS in plasma samples showed high specificity (90.7-100%) for almost all genomic alterations. Compared with FISH (gene copy number [GCN] ≥10), the overall percent agreement of tissue NGS, optimized tissue NGS (GCN ≥ 8.63), plasma NGS, and plasma ddPCR for MET amplification were 75.0% (27/36), 100% (36/36), 88.9% (32/36), and 94.4% (34/36), respectively. This study represents the largest-scale, prospective study with paired tissue and plasma samples to enable comprehensive analysis of GPS, providing a novel perspective into coalterations at the first-line treatment failure of osimertinib. A plasma sample serves as a supplement for identifying GPS when a tissue sample is unavailable. Moreover, the integration of FISH, NGS, and ddPCR provided a comprehensive assessment of MET amplification.
{"title":"A prospective, multicenter, comprehensive genomic profile signature study in patients with EGFR-mutant advanced non-small cell lung cancer at the first-line treatment failure of osimertinib.","authors":"Yuankai Shi, Dongqing Lv, Weineng Feng, Shuoyan Liu, Puyuan Xing, Yan Yu, Jun Yin, Xiubao Ren, Junqiang Zhang, Gaohua Han, Yongchang Zhang, Shundong Cang, Jun Chen, Enguo Chen, Lingxin Meng, Yong Zhang","doi":"10.1038/s41392-025-02481-8","DOIUrl":"10.1038/s41392-025-02481-8","url":null,"abstract":"<p><p>Osimertinib, the first approved third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), exhibits notable efficacy in EGFR-mutant non-small cell lung cancer (NSCLC). This is a prospective, multicenter, comprehensive genomic profile signature (GPS) study in paired tissue and plasma samples from 149 patients with advanced NSCLC harboring EGFR exon 19 deletion (Ex19del) or L858R mutation at the first-line treatment failure of osimertinib (NCT05219162). Next-generation sequencing (NGS) was used for comprehensive GPS analysis of paired tissue and plasma samples. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used for tissue samples, while droplet digital polymerase chain reaction (ddPCR) and NGS were used for plasma samples to perform a concordance analysis of MET amplification. At the first-line treatment failure of osimertinib (study entry), EGFR alterations in tissue samples included EGFR Ex19del (49.0%, 73/149), EGFR L858R mutation (43.0%, 64/149), EGFR amplification (32.9%, 49/149), EGFR L718Q/V mutation (4.7%, 7/149), and EGFR C797S mutation (3.4%, 5/149); bypass signaling activation and downstream pathway activation alterations included TP53 mutation (69.8%, 104/149) and MET amplification (30.9%, 46/149). Among the 136 patients with EGFR Ex19del/L858R mutation in tissue samples, 72.1% (98/136), 35.3% (48/136), and 32.4% (44/136) had TP53 mutations, EGFR amplification, and MET amplification, respectively. Taking tissue samples as references, the GPS in plasma samples showed high specificity (90.7-100%) for almost all genomic alterations. Compared with FISH (gene copy number [GCN] ≥10), the overall percent agreement of tissue NGS, optimized tissue NGS (GCN ≥ 8.63), plasma NGS, and plasma ddPCR for MET amplification were 75.0% (27/36), 100% (36/36), 88.9% (32/36), and 94.4% (34/36), respectively. This study represents the largest-scale, prospective study with paired tissue and plasma samples to enable comprehensive analysis of GPS, providing a novel perspective into coalterations at the first-line treatment failure of osimertinib. A plasma sample serves as a supplement for identifying GPS when a tissue sample is unavailable. Moreover, the integration of FISH, NGS, and ddPCR provided a comprehensive assessment of MET amplification.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"393"},"PeriodicalIF":52.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655311","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：