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}
Radiation therapy (RT) is a key treatment strategy for lung cancer, yet its efficacy is frequently compromised by radioresistance. The combination of RT with targeted therapies enhances treatment outcomes for non-small cell lung cancer (NSCLC). This study aims to investigate new mechanisms of metastasis after RT for NSCLC and improve the durability of the benefits of radiotherapy for lung cancer patients. This integrative study utilized human NSCLC tissue arrays, bulk RNA-sequencing, CUT&Tag sequencing, and single-cell RNA-sequencing to identify gene alterations induced by RT. In vitro experiments and animal studies were used to investigate the role of Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis in post-RT metastasis of NSCLC. RT triggered the upregulation of JMJD6 in NSCLC tissues. This upregulation led to the activation of EHF and the subsequent transcription of pluripotency factor genes through the demethylation of H4R3me2s. JMJD6/EHF axis plays a critical role in NSCLC cell metastasis, potentially through the TGF-β/SMAD and AKT/ERK signaling pathways. These findings suggest JMJD6 as a potential therapeutic target to combat post-RT metastasis in NSCLC.
{"title":"Integrative analysis of non-small cell lung cancer identifies Jumonji domain-containing 6/ETS homologous factor axis as a target to overcome radioresistance.","authors":"Manni Wang,Li Xu,Aqu Alu,Peiheng Li,Jian Liu,Siyuan Chen,Xuemei He,Xuejiao Han,Li Yang,Qiang Pu,Xiawei Wei","doi":"10.1038/s41392-025-02471-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02471-w","url":null,"abstract":"Radiation therapy (RT) is a key treatment strategy for lung cancer, yet its efficacy is frequently compromised by radioresistance. The combination of RT with targeted therapies enhances treatment outcomes for non-small cell lung cancer (NSCLC). This study aims to investigate new mechanisms of metastasis after RT for NSCLC and improve the durability of the benefits of radiotherapy for lung cancer patients. This integrative study utilized human NSCLC tissue arrays, bulk RNA-sequencing, CUT&Tag sequencing, and single-cell RNA-sequencing to identify gene alterations induced by RT. In vitro experiments and animal studies were used to investigate the role of Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis in post-RT metastasis of NSCLC. RT triggered the upregulation of JMJD6 in NSCLC tissues. This upregulation led to the activation of EHF and the subsequent transcription of pluripotency factor genes through the demethylation of H4R3me2s. JMJD6/EHF axis plays a critical role in NSCLC cell metastasis, potentially through the TGF-β/SMAD and AKT/ERK signaling pathways. These findings suggest JMJD6 as a potential therapeutic target to combat post-RT metastasis in NSCLC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"391"},"PeriodicalIF":39.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644893","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 role of preoperative anti-PD-1 antibody (pembrolizumab) plus chemoradiotherapy (PPCT) in locally advanced, resectable esophageal squamous cell carcinoma (ESCC) is still unclear. We aimed to investigate the therapeutic effect and safety of PPCT followed by surgery in this study (NCT03792347, NCT04435197). Patients with histologically confirmed, locally advanced, and surgically resectable ESCC were enrolled. They received PPCT with paclitaxel/carboplatin or nab-paclitaxel/carboplatin, followed by esophagectomy 4–6 weeks after treatment. The primary endpoint was the pathologic complete response (pCR) rate. Tumor specimens, blood samples and subcutaneous tumor mouse models were utilized to explore and validate the dynamic characteristics of the tumor microenvironment (TME) of ESCC after PPCT. Among the 143 patients enrolled, 140 received neoadjuvant treatment, and 125 underwent surgery. The pCR rate reached 43.2% (54/125). During neoadjuvant period, 75.7% (106/140) of patients experienced grade three or higher-grade adverse events. After a median follow-up of 17.4 months, patients showed a one-year disease-free survival rate of 91.1%, and an overall survival rate of 96.5%. Using scRNA-seq and cytokine profiling, we identified high IL-6 levels as a predictor of response to PPCT. In vivo experiment revealed that IL-6 neutralization enhanced the efficacy of immunotherapy by increasing CD4 + T-cell cytotoxicity. This is the first large-scale, multicenter, phase 1/2 trial reporting the short-term results of PPCT for locally advanced resectable ESCC. Although the short-term efficacy was not superior to that of neoadjuvant chemoradiotherapy, PPCT demonstrated acceptable safety and comparable one-year survival. We also revealed an association between the therapeutic response and the ability of anti-IL-6 blockade to enhance the efficacy of immunotherapy.
{"title":"Preoperative pembrolizumab (anti-PD-1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE-2)","authors":"Chengqiang Li, Yichao Han, Shengguang Zhao, Xiaozheng Kang, Yuyan Zheng, Yuqin Cao, Yan Yan, Liqiang Shi, Xipeng Wang, Tong Lu, Guowen Zou, Huan Li, Jiaming Che, Jie Xiang, Lianggang Zhu, Junbiao Hang, Yajie Zhang, Runsen Jin, Dingpei Han, Xueyu Chen, Hui Jing, Wei Guo, Zenghui Cheng, Liqin Zhao, Xiaoyan Chen, Bentong Yu, Jian Li, Bin Li, Yin Li, Hecheng Li","doi":"10.1038/s41392-025-02477-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02477-4","url":null,"abstract":"The role of preoperative anti-PD-1 antibody (pembrolizumab) plus chemoradiotherapy (PPCT) in locally advanced, resectable esophageal squamous cell carcinoma (ESCC) is still unclear. We aimed to investigate the therapeutic effect and safety of PPCT followed by surgery in this study (NCT03792347, NCT04435197). Patients with histologically confirmed, locally advanced, and surgically resectable ESCC were enrolled. They received PPCT with paclitaxel/carboplatin or nab-paclitaxel/carboplatin, followed by esophagectomy 4–6 weeks after treatment. The primary endpoint was the pathologic complete response (pCR) rate. Tumor specimens, blood samples and subcutaneous tumor mouse models were utilized to explore and validate the dynamic characteristics of the tumor microenvironment (TME) of ESCC after PPCT. Among the 143 patients enrolled, 140 received neoadjuvant treatment, and 125 underwent surgery. The pCR rate reached 43.2% (54/125). During neoadjuvant period, 75.7% (106/140) of patients experienced grade three or higher-grade adverse events. After a median follow-up of 17.4 months, patients showed a one-year disease-free survival rate of 91.1%, and an overall survival rate of 96.5%. Using scRNA-seq and cytokine profiling, we identified high IL-6 levels as a predictor of response to PPCT. In vivo experiment revealed that IL-6 neutralization enhanced the efficacy of immunotherapy by increasing CD4 <jats:sup>+</jats:sup> T-cell cytotoxicity. This is the first large-scale, multicenter, phase 1/2 trial reporting the short-term results of PPCT for locally advanced resectable ESCC. Although the short-term efficacy was not superior to that of neoadjuvant chemoradiotherapy, PPCT demonstrated acceptable safety and comparable one-year survival. We also revealed an association between the therapeutic response and the ability of anti-IL-6 blockade to enhance the efficacy of immunotherapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"3 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611263","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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