Pub Date : 2025-12-16DOI: 10.1016/j.drup.2025.101344
Zhendong Deng , Yongxin Wei , Shuang Liu , Lu Chen , Xuhui Wang , Zihao Liu , Lingling Liu , Yaohui Wang , Xinyu Lv , Shanliang Sun , Haiwen Ni , Chunyan Gu , Ye Yang
Aims
Transcriptional dysregulation by aberrant transcription factors (TFs) is a key driver of drug resistance. Resistance to adriamycin (ADR) frequently develops following first-line treatment for multiple myeloma (MM). This study aims to identify novel TFs associated with ADR resistance in MM and to elucidate their underlying mechanisms.
Methods
We employed a protein chip assay with FITC-labeled celastrol and identified the deformed epidermal autoregulatory factor 1 (DEAF1) as a potential target in MM. High-throughput sequencing was performed to identify DEAF1 downstream targets. Both in vivo and in vitro models were utilized to delineate the role of DEAF1 in MM cell proliferation and ADR resistance.
Results
High DEAF1 expression was associated with poor prognosis in MM patients, and was found to promote MM cell proliferation and induce ADR resistance. Mechanistically, DEAF1 directly binds to the RAD50 promoter via its SAND domain, upregulating RAD50 expression and consequently activating the ATM pathway. Furthermore, DEAF1 recruited AP-2-alpha (AP-2α) through its MYND domain, leading to the downregulation of tyrosine-protein kinase Fer (FER). This downregulation impaired FER-mediated phosphorylation of GSDME, which is known to enhance the cleavage efficiency of GSDME by caspase-3. Additionally, celastrol synergized with ADR to inhibit MM cell viability by disrupting the binding of DEAF1 to the promoters of its target genes.
Conclusions
Our findings demonstrate that DEAF1 attenuates ADR-induced apoptosis and pyroptosis in MM by enhancing DNA damage repair and suppressing GSDME cleavage via the FER/GSDME axis. This study provides a novel therapeutic target for the treatment of MM.
{"title":"DEAF1 confers resistance to adriamycin-induced apoptosis and pyroptosis in multiple myeloma","authors":"Zhendong Deng , Yongxin Wei , Shuang Liu , Lu Chen , Xuhui Wang , Zihao Liu , Lingling Liu , Yaohui Wang , Xinyu Lv , Shanliang Sun , Haiwen Ni , Chunyan Gu , Ye Yang","doi":"10.1016/j.drup.2025.101344","DOIUrl":"10.1016/j.drup.2025.101344","url":null,"abstract":"<div><h3>Aims</h3><div>Transcriptional dysregulation by aberrant transcription factors (TFs) is a key driver of drug resistance. Resistance to adriamycin (ADR) frequently develops following first-line treatment for multiple myeloma (MM). This study aims to identify novel TFs associated with ADR resistance in MM and to elucidate their underlying mechanisms.</div></div><div><h3>Methods</h3><div>We employed a protein chip assay with FITC-labeled celastrol and identified the deformed epidermal autoregulatory factor 1 (DEAF1) as a potential target in MM. High-throughput sequencing was performed to identify DEAF1 downstream targets. Both <em>in vivo</em> and <em>in vitro</em> models were utilized to delineate the role of DEAF1 in MM cell proliferation and ADR resistance.</div></div><div><h3>Results</h3><div>High DEAF1 expression was associated with poor prognosis in MM patients, and was found to promote MM cell proliferation and induce ADR resistance. Mechanistically, DEAF1 directly binds to the RAD50 promoter via its SAND domain, upregulating RAD50 expression and consequently activating the ATM pathway. Furthermore, DEAF1 recruited AP-2-alpha (AP-2α) through its MYND domain, leading to the downregulation of tyrosine-protein kinase Fer (FER). This downregulation impaired FER-mediated phosphorylation of GSDME, which is known to enhance the cleavage efficiency of GSDME by caspase-3. Additionally, celastrol synergized with ADR to inhibit MM cell viability by disrupting the binding of DEAF1 to the promoters of its target genes.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that DEAF1 attenuates ADR-induced apoptosis and pyroptosis in MM by enhancing DNA damage repair and suppressing GSDME cleavage via the FER/GSDME axis. This study provides a novel therapeutic target for the treatment of MM.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101344"},"PeriodicalIF":21.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786001","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}
Epigenetic dysregulation is a significant factor contributing to cisplatin resistance in bladder cancer (BCa). Increasing studies indicated a synergistic effect of cisplatin and Entinostat, which is an FDA-approved histone deacetylases (HDAC) inhibitor, however, the underlying mechanisms of this effect remains unknown. Herein, the synergy of cisplatin and Entinostat was confirmed in BCa cells. Integrated RNA-seq and ATAC-seq analysis revealed that the combined regimen of cisplatin and Entinostat led to significant downregulation of platinum resistance and DNA damage repair-related pathways. We focused on the candidate gene dehydrogenase/reductase member 2 (DHRS2), and found that Entinostat counteracted cisplatin resistance via promoting histone H3K18 lactylation (H3K18la)-mediated DHRS2 upregulation and enhancing the nuclear translocation of DHRS2. DHRS2 downregulation promoted cisplatin resistance by upregulating aldo-keto reductase family 1 member C3 (AKR1C3), a key enzyme in androgen synthesis. Moreover, we validated a negative correlation between DHRS2 levels and AKR1C3 expression in clinical BCa samples. It was found that high DHRS2 and low AKR1C3 expression correlates with improved neoadjuvant chemotherapy (NAC) response. Furthermore, high DHRS2 predicts better survival specifically in male patients, indicating sex-specific androgen involvement. Overall, these findings elucidate the epigenetic mechanism underlying the cisplatin-sensitizing effect of Entinostat, and identifies the DHRS2–AKR1C3–androgen axis as a potential target, particularly for male patients.
{"title":"Entinostat overcomes cisplatin resistance in bladder cancer by promoting H3K18la-mediated DHRS2 expression and nuclear translocation to suppress the AKR1C3-androgen axis","authors":"Guanghui Xu , Minghao Zheng , Zhigang Wu , Tianlei Xie , Yuqin Li , Ganlin Hu , Shuting Fang , Jing Zhang , Wenli Diao , Wei Zhao , Hongqian Guo , Junlong Zhuang","doi":"10.1016/j.drup.2025.101343","DOIUrl":"10.1016/j.drup.2025.101343","url":null,"abstract":"<div><div>Epigenetic dysregulation is a significant factor contributing to cisplatin resistance in bladder cancer (BCa). Increasing studies indicated a synergistic effect of cisplatin and Entinostat, which is an FDA-approved histone deacetylases (HDAC) inhibitor, however, the underlying mechanisms of this effect remains unknown. Herein, the synergy of cisplatin and Entinostat was confirmed in BCa cells. Integrated RNA-seq and ATAC-seq analysis revealed that the combined regimen of cisplatin and Entinostat led to significant downregulation of platinum resistance and DNA damage repair-related pathways. We focused on the candidate gene dehydrogenase/reductase member 2 (DHRS2), and found that Entinostat counteracted cisplatin resistance via promoting histone H3K18 lactylation (H3K18la)-mediated DHRS2 upregulation and enhancing the nuclear translocation of DHRS2. DHRS2 downregulation promoted cisplatin resistance by upregulating aldo-keto reductase family 1 member C3 (AKR1C3), a key enzyme in androgen synthesis. Moreover, we validated a negative correlation between DHRS2 levels and AKR1C3 expression in clinical BCa samples. It was found that high DHRS2 and low AKR1C3 expression correlates with improved neoadjuvant chemotherapy (NAC) response. Furthermore, high DHRS2 predicts better survival specifically in male patients, indicating sex-specific androgen involvement. Overall, these findings elucidate the epigenetic mechanism underlying the cisplatin-sensitizing effect of Entinostat, and identifies the DHRS2–AKR1C3–androgen axis as a potential target, particularly for male patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101343"},"PeriodicalIF":21.7,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730716","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 : 2025-12-08DOI: 10.1016/j.drup.2025.101342
Yuxi Lin , Feng Zhang , Weimin Guo , Jiaxin Guo , Xu Qiu , Yuelin Sun , Rong Li , Zihao Pan , Wentao Zhong , Min Yu , Jun Zheng , Jingwen Peng , Weifeng Hong
The emergence of resistance to tyrosine kinase inhibitors (TKIs) compromises their clinical benefits in patients with hepatocellular carcinoma (HCC), in part due to adaptive responses triggered by tumor hypoxia. In this study, we leverage hyperbaric oxygen (HBO) therapy as a sensitizing strategy in sorafenib-resistant HCC. We demonstrate that HBO significantly enhances the anti-tumor effect of sorafenib by stimulating calcium transfer from the endoplasmic reticulum (ER) to mitochondria, resulting in ER stress and mitochondrial dysfunction. Mechanistically, we show that hypoxia upregulates HNF4A, a transcriptional suppressor of RCN1, and HBO therapy effectively inhibits this hypoxia-driven HNF4A/RCN1 axis. Downregulation of RCN1, a calcium-binding protein overexpressed in sorafenib-resistant HCC, strengthens ER-mitochondria coupling. Subsequently, RCN1 suppression attenuates its interaction with IP3R1 through the EFh1/2 domain, facilitating IP3R1-GRP75 dissociation and the activation of mitochondrial calcium-uptake machinery. Using its EF-hand domains, RCN1 senses fluctuations in ER calcium concentration and accordingly employs a feedback mechanism to fine-tune its binding to IP3R1. In xenograft and spontaneous models, combined HBO-TKIs treatment delays tumor progression and modulates the HNF4A/RCN1 axis. Taken together, our findings elucidate a hitherto uncharacterized role of HBO in regulating ER-mitochondria calcium homeostasis and support its clinical application as an adjunctive therapy in TKI-resistant HCC.
{"title":"Hyperbaric oxygen targets RCN1 to modulate ER-mitochondria crosstalk and ameliorate sorafenib resistance in hepatocellular carcinoma","authors":"Yuxi Lin , Feng Zhang , Weimin Guo , Jiaxin Guo , Xu Qiu , Yuelin Sun , Rong Li , Zihao Pan , Wentao Zhong , Min Yu , Jun Zheng , Jingwen Peng , Weifeng Hong","doi":"10.1016/j.drup.2025.101342","DOIUrl":"10.1016/j.drup.2025.101342","url":null,"abstract":"<div><div>The emergence of resistance to tyrosine kinase inhibitors (TKIs) compromises their clinical benefits in patients with hepatocellular carcinoma (HCC), in part due to adaptive responses triggered by tumor hypoxia. In this study, we leverage hyperbaric oxygen (HBO) therapy as a sensitizing strategy in sorafenib-resistant HCC. We demonstrate that HBO significantly enhances the anti-tumor effect of sorafenib by stimulating calcium transfer from the endoplasmic reticulum (ER) to mitochondria, resulting in ER stress and mitochondrial dysfunction. Mechanistically, we show that hypoxia upregulates HNF4A, a transcriptional suppressor of RCN1, and HBO therapy effectively inhibits this hypoxia-driven HNF4A/RCN1 axis. Downregulation of RCN1, a calcium-binding protein overexpressed in sorafenib-resistant HCC, strengthens ER-mitochondria coupling. Subsequently, RCN1 suppression attenuates its interaction with IP3R1 through the EFh1/2 domain, facilitating IP3R1-GRP75 dissociation and the activation of mitochondrial calcium-uptake machinery. Using its EF-hand domains, RCN1 senses fluctuations in ER calcium concentration and accordingly employs a feedback mechanism to fine-tune its binding to IP3R1. In xenograft and spontaneous models, combined HBO-TKIs treatment delays tumor progression and modulates the HNF4A/RCN1 axis. Taken together, our findings elucidate a hitherto uncharacterized role of HBO in regulating ER-mitochondria calcium homeostasis and support its clinical application as an adjunctive therapy in TKI-resistant HCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101342"},"PeriodicalIF":21.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731944","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 : 2025-12-04DOI: 10.1016/j.drup.2025.101339
Mengyuan Wu , Xu Huang , Miao Lin , Zhiyun Duan , Zitao Jian , Runze You , Peiyi Xie , Zhiwei Wu , Siyun Lin , Shaoyuan Zhang , Wenyi Xu , Heng Jiao , Han Tang , Lei Guo , Hao Wang , Weigang Guo , Lijie Tan
Aims
Metastatic progression and treatment resistance determine poor prognostic outcomes of patients with esophageal squamous cellular carcinoma (ESCC), highlighting the urgent need to understand the molecular mechanisms behind this. Reticulocalbin 2 (RCN2) is a calcium-binding protein localized in the endoplasmic reticulum lumen, which mediates tumor progression in various cancer types. However, the role of RCN2 in ESCC remains unexplored.
Methods
The influence of RCN2 on ESCC progression, metastasis, and cisplatin (CDDP) resistance was assessed both in vitro and in vivo. The downstream regulatory mechanism associated with RCN2 was screened through RNA-seq, TMT 10X mass spectrometry analysis, and LC-MS/MS analysis, which was further validated through Western blot, immunoprecipitation, immunofluorescence, GST pull-down assay, and rescue experiments.
Results
We observed high RCN2 expression in ESCC tumor tissues from patients with metastasis, which is correlated with a higher risk of metastasis and worse survival. PPP2CA, a catalytic subunit of protein phosphatase 2 A (PP2A), and ubiquitin protein ligase E3 component N-recognin 5 (UBR5) are determined as novel RCN2 functioning interactors. Mechanistically, RCN2 facilitates PPP2CA ubiquitination and degradation dependent on the HECT domain of UBR5, thereby activating the PI3K-AKT signaling pathway. Furthermore, the activated RCN2-PPP2CA-PI3K-AKT axis is validated in clinical specimens of ESCC. Finally, targeted suppression of RCN2 synergized with CDDP treatment to prevent tumor growth and metastasis in subcutaneous and lung metastasis models.
Conclusions
Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.
{"title":"RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation","authors":"Mengyuan Wu , Xu Huang , Miao Lin , Zhiyun Duan , Zitao Jian , Runze You , Peiyi Xie , Zhiwei Wu , Siyun Lin , Shaoyuan Zhang , Wenyi Xu , Heng Jiao , Han Tang , Lei Guo , Hao Wang , Weigang Guo , Lijie Tan","doi":"10.1016/j.drup.2025.101339","DOIUrl":"10.1016/j.drup.2025.101339","url":null,"abstract":"<div><h3>Aims</h3><div>Metastatic progression and treatment resistance determine poor prognostic outcomes of patients with esophageal squamous cellular carcinoma (ESCC), highlighting the urgent need to understand the molecular mechanisms behind this. Reticulocalbin 2 (RCN2) is a calcium-binding protein localized in the endoplasmic reticulum lumen, which mediates tumor progression in various cancer types. However, the role of RCN2 in ESCC remains unexplored.</div></div><div><h3>Methods</h3><div>The influence of RCN2 on ESCC progression, metastasis, and cisplatin (CDDP) resistance was assessed both <em>in vitro</em> and <em>in vivo</em>. The downstream regulatory mechanism associated with RCN2 was screened through RNA-seq, TMT 10X mass spectrometry analysis, and LC-MS/MS analysis, which was further validated through Western blot, immunoprecipitation, immunofluorescence, GST pull-down assay, and rescue experiments.</div></div><div><h3>Results</h3><div>We observed high RCN2 expression in ESCC tumor tissues from patients with metastasis, which is correlated with a higher risk of metastasis and worse survival. PPP2CA, a catalytic subunit of protein phosphatase 2 A (PP2A), and ubiquitin protein ligase E3 component N-recognin 5 (UBR5) are determined as novel RCN2 functioning interactors. Mechanistically, RCN2 facilitates PPP2CA ubiquitination and degradation dependent on the HECT domain of UBR5, thereby activating the PI3K-AKT signaling pathway. Furthermore, the activated RCN2-PPP2CA-PI3K-AKT axis is validated in clinical specimens of ESCC. Finally, targeted suppression of RCN2 synergized with CDDP treatment to prevent tumor growth and metastasis in subcutaneous and lung metastasis models.</div></div><div><h3>Conclusions</h3><div>Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101339"},"PeriodicalIF":21.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689546","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 : 2025-12-02DOI: 10.1016/j.drup.2025.101332
Diaoyi Tan , Yuzhong Ye , Daojia Miao , Chuanyi Zhao , Songming Wu , Jian Shi , Junkai Yang , Kanglin Fang , Feiyi Lu , Qingyang Lv , Jinshuo Gong , Hongmei Yang , Wen Xiao , Zhiyong Xiong , Xiaoping Zhang , Hailong Ruan
Background
Targeted therapy is the first-line treatment for patients with metastatic renal cell carcinoma (RCC), with vascular endothelial growth factor receptor inhibitors (VEGFRis) constituting the bulk of regimens used. Although the repertoire of VEGFRis for RCC now spans from sunitinib to cabozantinib, resistance to treatments has emerged as a common and prominent challenge. Thus, identifying novel therapeutic targets has become essential for enhancing the antitumor efficacy of current treatments and inhibiting RCC progression.
Method
To investigate the potential mechanisms underlying VEGFRi resistance in RCC, we performed a genome-wide CRISPR/Cas9 library screen under sunitinib and cabozantinib treatment and identified UBL3 as a key driver of VEGFRi resistance in RCC cells. The critical role of UBL3 in promoting VEGFRi resistance was validated using CCK8 assays, flow cytometry, TUNEL assays, and bioinformatics analyses. To elucidate the molecular mechanisms underlying UBL3, we utilized western blotting, RNA sequencing, chromatin immunoprecipitation, small extracellular vesicles (sEVs) isolation, and Astral-DIA proteomics. The contribution of UBL3 to VEGFRi resistance was further confirmed through comprehensive in vitro and in vivo experiments.
Results
UBL3 was confirmed to suppress apoptosis and promote VEGFRi resistance through NOTCH signaling activation. Further investigations highlighted the importance of NOTCH signaling in VEGFRi resistance in RCC via the NOTCH-PTEN-AKT and NOTCH-FOS pathways and revealed the mechanisms by which UBL3 activated NOTCH signaling. On the one hand, UBL3 formed complex with NOTCH2 and ADAM17 simultaneously, accelerating ADAM17-mediated cleavage of NOTCH2. On the other hand, UBL3-modified NOTCH2 was sorted into sEVs, which were taken up by recipient cells, activating NOTCH signaling and thereby transmitting VEGFRi resistance. Finally, lipid nanoparticle-mediated delivery of the CRISPR/Cas9 knockout system targeting UBL3 effectively restored the sensitivity of RCC tumors to VEGFRis.
Conclusion
This study emphasized the importance of UBL3 in VEGFRi resistance in RCC and proposed that UBL3 activated NOTCH signaling through two distinct pathways, thereby suppressing cancer apoptosis and promoting resistance to VEGFRis. These findings provided a solid scientific foundation and paved the way for the development of novel therapeutic strategies for patients with advanced RCC.
{"title":"UBL3 governs VEGFR inhibitor resistance by activating NOTCH signaling in renal cell carcinoma","authors":"Diaoyi Tan , Yuzhong Ye , Daojia Miao , Chuanyi Zhao , Songming Wu , Jian Shi , Junkai Yang , Kanglin Fang , Feiyi Lu , Qingyang Lv , Jinshuo Gong , Hongmei Yang , Wen Xiao , Zhiyong Xiong , Xiaoping Zhang , Hailong Ruan","doi":"10.1016/j.drup.2025.101332","DOIUrl":"10.1016/j.drup.2025.101332","url":null,"abstract":"<div><h3>Background</h3><div>Targeted therapy is the first-line treatment for patients with metastatic renal cell carcinoma (RCC), with vascular endothelial growth factor receptor inhibitors (VEGFRis) constituting the bulk of regimens used. Although the repertoire of VEGFRis for RCC now spans from sunitinib to cabozantinib, resistance to treatments has emerged as a common and prominent challenge. Thus, identifying novel therapeutic targets has become essential for enhancing the antitumor efficacy of current treatments and inhibiting RCC progression.</div></div><div><h3>Method</h3><div>To investigate the potential mechanisms underlying VEGFRi resistance in RCC, we performed a genome-wide CRISPR/Cas9 library screen under sunitinib and cabozantinib treatment and identified UBL3 as a key driver of VEGFRi resistance in RCC cells. The critical role of UBL3 in promoting VEGFRi resistance was validated using CCK8 assays, flow cytometry, TUNEL assays, and bioinformatics analyses. To elucidate the molecular mechanisms underlying UBL3, we utilized western blotting, RNA sequencing, chromatin immunoprecipitation, small extracellular vesicles (sEVs) isolation, and Astral-DIA proteomics. The contribution of UBL3 to VEGFRi resistance was further confirmed through comprehensive in vitro and in vivo experiments.</div></div><div><h3>Results</h3><div>UBL3 was confirmed to suppress apoptosis and promote VEGFRi resistance through NOTCH signaling activation. Further investigations highlighted the importance of NOTCH signaling in VEGFRi resistance in RCC via the NOTCH-PTEN-AKT and NOTCH-FOS pathways and revealed the mechanisms by which UBL3 activated NOTCH signaling. On the one hand, UBL3 formed complex with NOTCH2 and ADAM17 simultaneously, accelerating ADAM17-mediated cleavage of NOTCH2. On the other hand, UBL3-modified NOTCH2 was sorted into sEVs, which were taken up by recipient cells, activating NOTCH signaling and thereby transmitting VEGFRi resistance. Finally, lipid nanoparticle-mediated delivery of the CRISPR/Cas9 knockout system targeting UBL3 effectively restored the sensitivity of RCC tumors to VEGFRis.</div></div><div><h3>Conclusion</h3><div>This study emphasized the importance of UBL3 in VEGFRi resistance in RCC and proposed that UBL3 activated NOTCH signaling through two distinct pathways, thereby suppressing cancer apoptosis and promoting resistance to VEGFRis. These findings provided a solid scientific foundation and paved the way for the development of novel therapeutic strategies for patients with advanced RCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101332"},"PeriodicalIF":21.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657171","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 : 2025-11-29DOI: 10.1016/j.drup.2025.101328
Ryan McWhorter , Salem Chouaib , Benjamin Bonavida
The Raf kinase inhibitor protein (RKIP) functions as both a metastasis suppressor and immune enhancer, exerting its influence over several key oncogenic signaling pathways, including the MAPK, NF-κB, and PI3K pathways. Recent studies have highlighted a potential interplay between RKIP and hypoxia-inducible factors (HIFs), particularly in the hypoxic tumor microenvironment (TME). Hypoxia is known to reprogram cellular metabolism, enhance angiogenesis, and facilitate immune escape. Through analysis of cross-talk signaling pathways between RKIP and HIFs, we establish the presence of a dysregulated RKIP-hypoxia axis in cancer. Notably, many cancers simultaneously express low levels of RKIP and high levels of HIFs an expression pattern that strongly correlates with the emergence of immune evasion mechanisms. Herein, we report on the mechanisms by which this dysregulated axis mediates immune evasion. These include the molecular regulations of RKIP and HIFs expressions, and the low expression of RKIP and high expression of HIFs in several cancers. We report on the mechanisms underlying immune evasion by the RKIP-hypoxia axis by examining various factors intimately involved in immune evasion, such as the upregulation of PD-L1, matrix metalloproteinases (MMPs), anti-apoptotic molecules, CD47, and the enhanced frequencies of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophage (TAM) polarization, and decreased antigen presentation. Thus, hypoxia-induced repression of RKIP establishes a feedforward loop that sustains immune evasion and tumor aggressiveness. Therapeutically, we propose that targeting the RKIP-hypoxia axis offers a new strategy to restore immune surveillance and counteract tumor progression. We present various means to target the inhibition of hypoxia as well as the induction of RKIP. Elucidating the molecular crosstalk between RKIP and hypoxic stress responses opens a new paradigm for strategies that enhance the efficacy of immunotherapies and overcome tumor resistance.
{"title":"The implied dysregulated RKIP-hypoxia axis in cancer and immune evasion: Clinical implications","authors":"Ryan McWhorter , Salem Chouaib , Benjamin Bonavida","doi":"10.1016/j.drup.2025.101328","DOIUrl":"10.1016/j.drup.2025.101328","url":null,"abstract":"<div><div>The Raf kinase inhibitor protein (RKIP) functions as both a metastasis suppressor and immune enhancer, exerting its influence over several key oncogenic signaling pathways, including the MAPK, NF-κB, and PI3K pathways. Recent studies have highlighted a potential interplay between RKIP and hypoxia-inducible factors (HIFs), particularly in the hypoxic tumor microenvironment (TME). Hypoxia is known to reprogram cellular metabolism, enhance angiogenesis, and facilitate immune escape. Through analysis of cross-talk signaling pathways between RKIP and HIFs, we establish the presence of a dysregulated RKIP-hypoxia axis in cancer. Notably, many cancers simultaneously express low levels of RKIP and high levels of HIFs <img> an expression pattern that strongly correlates with the emergence of immune evasion mechanisms. Herein, we report on the mechanisms by which this dysregulated axis mediates immune evasion. These include the molecular regulations of RKIP and HIFs expressions, and the low expression of RKIP and high expression of HIFs in several cancers. We report on the mechanisms underlying immune evasion by the RKIP-hypoxia axis by examining various factors intimately involved in immune evasion, such as the upregulation of PD-L1, matrix metalloproteinases (MMPs), anti-apoptotic molecules, CD47, and the enhanced frequencies of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophage (TAM) polarization, and decreased antigen presentation. Thus, hypoxia-induced repression of RKIP establishes a feedforward loop that sustains immune evasion and tumor aggressiveness. Therapeutically, we propose that targeting the RKIP-hypoxia axis offers a new strategy to restore immune surveillance and counteract tumor progression. We present various means to target the inhibition of hypoxia as well as the induction of RKIP. Elucidating the molecular crosstalk between RKIP and hypoxic stress responses opens a new paradigm for strategies that enhance the efficacy of immunotherapies and overcome tumor resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101328"},"PeriodicalIF":21.7,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613768","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 : 2025-11-28DOI: 10.1016/j.drup.2025.101330
Yuqing Wang , Min Deng , Haipeng Lei , Kai Miao , Xiaodong Shu , Jianjie Li , Dongyang Tang , Yangyang Feng , Sek Man Su , Ling Li , Yanjie Wang , Heng Sun , Fangyuan Shao , Tingting An , Xiaoling Li , Fanlin Zhou , Tingxiu Xiang , Xiaoling Xu , Chuxia Deng
Platinum-based chemotherapy remains a cornerstone of cancer treatment; however, its clinical efficacy is frequently compromised by acquired drug resistance. Our study elucidated a novel resistance mechanism mediated by LARS2 signaling in mammary tumors. Through comprehensive multi-omics analyses of cancer patients, mouse models, and functional validation, we demonstrated that platinum treatment upregulates LARS2 via a danger-triggered host response during resistant tumor progression, concomitant with increased chromatin accessibility. This signaling drives drug resistance through two key mechanisms: enrichment of cancer stem cells and promotion of TGF-β-mediated immunosuppression, as evidenced by M2 macrophage polarization and CD8+ T cell exhaustion. Importantly, we developed an effective therapeutic strategy combining carboplatin with LARS2 signaling pathway inhibition, which successfully reversed platinum resistance and restored PD-1 checkpoint blockade sensitivity in preclinical models. These findings not only advance our understanding of chemotherapy resistance, but also provide a translatable therapeutic framework for breast cancer and other platinum-treated malignancies.
{"title":"Lars2-signaling mediates platinum resistance by accumulating cancer stem cell population and suppressing anti-tumor immunity","authors":"Yuqing Wang , Min Deng , Haipeng Lei , Kai Miao , Xiaodong Shu , Jianjie Li , Dongyang Tang , Yangyang Feng , Sek Man Su , Ling Li , Yanjie Wang , Heng Sun , Fangyuan Shao , Tingting An , Xiaoling Li , Fanlin Zhou , Tingxiu Xiang , Xiaoling Xu , Chuxia Deng","doi":"10.1016/j.drup.2025.101330","DOIUrl":"10.1016/j.drup.2025.101330","url":null,"abstract":"<div><div>Platinum-based chemotherapy remains a cornerstone of cancer treatment; however, its clinical efficacy is frequently compromised by acquired drug resistance. Our study elucidated a novel resistance mechanism mediated by LARS2 signaling in mammary tumors. Through comprehensive multi-omics analyses of cancer patients, mouse models, and functional validation, we demonstrated that platinum treatment upregulates LARS2 via a danger-triggered host response during resistant tumor progression, concomitant with increased chromatin accessibility. This signaling drives drug resistance through two key mechanisms: enrichment of cancer stem cells and promotion of TGF-β-mediated immunosuppression, as evidenced by M2 macrophage polarization and CD8<sup>+</sup> T cell exhaustion. Importantly, we developed an effective therapeutic strategy combining carboplatin with LARS2 signaling pathway inhibition, which successfully reversed platinum resistance and restored PD-1 checkpoint blockade sensitivity in preclinical models. These findings not only advance our understanding of chemotherapy resistance, but also provide a translatable therapeutic framework for breast cancer and other platinum-treated malignancies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101330"},"PeriodicalIF":21.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613764","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 : 2025-11-25DOI: 10.1016/j.drup.2025.101331
Ting Yu , Dandan Peng , Xiao Liang , Wen Nie , Huaicheng Tan , Siyuan Chen , Huashan Shi , Yuquan Wei , Xiawei Wei
Aims
Glucocorticoids (GCs) such as dexamethasone are routinely used in patients to alleviate side effects of chemotherapeutic agents or symptoms caused by advanced cancer. However, growing evidences have found glucocorticoids-induced chemoresistance in solid tumors, while the potential effects and underlying mechanisms are still remained unclearly. This study aimed to reveal the underlying mechanism of glucocorticoids-induced chemoresistance in lung cancer.
Methods
Effects of dexamethasone on chemotherapy efficiency and stemness properties were tested both in vitro and in vivo assays. Underlying mechanism of dexamethasone was revealed by western blot, protein immunoprecipitation, molecular dynamics simulation, high-resolution mass spectrometry detection and RNA-sequencing. Prognostic value of glucocorticoid receptor (GR) activation in lung cancer patients was assessed through transcriptomic analyses of public datasets.
Results
Pre-treatment with dexamethasone significantly suppressed the apoptosis mediated by multiple chemotherapeutic agents in lung cancer cells. Pulmonary metastatic mouse models showed dexamethasone pre-treatment markedly reduced the anti-tumor efficiency of paclitaxel. Stemness-related properties of lung cancer were significantly improved after dexamethasone treatment, which manifested with enhanced self-renewal capability, improved chemoresistance, and increased tumor initiating potential in vivo. Moreover, we revealed the chemoresistance and stemness properties induced by dexamethasone were depended on GR-mediated nuclear translocation of β-catenin. The N-terminal domain (NTD) and activation function 2 (AF2) region of GR mediated the major contribution in the interaction with β-catenin. Analyses of clinical samples from TCGA-LUAD and GEO datasets demonstrated GR activation was associated with worse survival and less benefits from chemotherapy in lung cancer patients.
Conclusions
These results revealed dexamethasone could promote chemoresistance and stemness in lung cancer by inducing nuclear-translocation of GR/β-catenin complex. In the long run, more cautions are needed when glucocorticoids are prescribed to patients during chemotherapy.
{"title":"Glucocorticoid receptor activated by dexamethasone promotes the chemoresistance and stemness of lung cancer","authors":"Ting Yu , Dandan Peng , Xiao Liang , Wen Nie , Huaicheng Tan , Siyuan Chen , Huashan Shi , Yuquan Wei , Xiawei Wei","doi":"10.1016/j.drup.2025.101331","DOIUrl":"10.1016/j.drup.2025.101331","url":null,"abstract":"<div><h3>Aims</h3><div>Glucocorticoids (GCs) such as dexamethasone are routinely used in patients to alleviate side effects of chemotherapeutic agents or symptoms caused by advanced cancer. However, growing evidences have found glucocorticoids-induced chemoresistance in solid tumors, while the potential effects and underlying mechanisms are still remained unclearly. This study aimed to reveal the underlying mechanism of glucocorticoids-induced chemoresistance in lung cancer.</div></div><div><h3>Methods</h3><div>Effects of dexamethasone on chemotherapy efficiency and stemness properties were tested both <em>in vitro</em> and <em>in vivo</em> assays. Underlying mechanism of dexamethasone was revealed by western blot, protein immunoprecipitation, molecular dynamics simulation, high-resolution mass spectrometry detection and RNA-sequencing. Prognostic value of glucocorticoid receptor (GR) activation in lung cancer patients was assessed through transcriptomic analyses of public datasets.</div></div><div><h3>Results</h3><div>Pre-treatment with dexamethasone significantly suppressed the apoptosis mediated by multiple chemotherapeutic agents in lung cancer cells. Pulmonary metastatic mouse models showed dexamethasone pre-treatment markedly reduced the anti-tumor efficiency of paclitaxel. Stemness-related properties of lung cancer were significantly improved after dexamethasone treatment, which manifested with enhanced self-renewal capability, improved chemoresistance, and increased tumor initiating potential <em>in vivo</em>. Moreover, we revealed the chemoresistance and stemness properties induced by dexamethasone were depended on GR-mediated nuclear translocation of β-catenin. The N-terminal domain (NTD) and activation function 2 (AF2) region of GR mediated the major contribution in the interaction with β-catenin. Analyses of clinical samples from TCGA-LUAD and GEO datasets demonstrated GR activation was associated with worse survival and less benefits from chemotherapy in lung cancer patients.</div></div><div><h3>Conclusions</h3><div>These results revealed dexamethasone could promote chemoresistance and stemness in lung cancer by inducing nuclear-translocation of GR/β-catenin complex. In the long run, more cautions are needed when glucocorticoids are prescribed to patients during chemotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101331"},"PeriodicalIF":21.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598828","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 : 2025-11-22DOI: 10.1016/j.drup.2025.101329
Wei Gao , Jianliang Huang , Kun Deng , Xiang Lin , Xinmiao Long , Xuetong Li , Meng Huang , Xiangyu Wang , Xiaoling She , Qing Liu , Minghua Wu
Aims
Glioblastoma (GBM), particularly mesenchymal and recurrent GBM, often develops resistance to temozolomide (TMZ) and is characterized by extensive infiltration of monocyte-derived macrophages (MDM), which contributes to treatment failure. However, the mechanisms through which TMZ-resistant GBM recruits MDM remain poorly understood. This study aims to investigate the molecular drivers of MDM infiltration in the context of TMZ resistance and to identify potential therapeutic targets to disrupt this process.
Methods
Patient-derived GBM organoid (GBO) was utilized as a model system. We performed molecular profiling to identify genes upregulated in TMZ-resistant recurrent GBO. Endothelial cells (ECs) cultures and preclinical GBM models were used to examine disruption of tight junctions and monocyte infiltration. Mechanistic studies employed genetic knockdown, pharmacological inhibition, and assays, including Chromatin immunoprecipitation-quantitative PCR, Western blot, and immunostaining, to validate pathway activity and protein interactions.
Results
COL6A1 (Collagen type VI alpha 1 chain) was significantly upregulated in TMZ-resistant recurrent GBO and associated with poor survival. COL6A1 is bound to ITGB1 (Integrin beta-1) on ECs, leading to disruption of tight junctions via UBD (Ubiquitin-like modifier D)-mediated degradation of claudin-5. Furthermore, COL6A1 activated the FAK/SRC/Hippo/YAP signaling axis, which promoted lactylation of the transcription factor IKZF1 (IKAROS family zinc finger 1) at lysine 255. Lactylated IKZF1 translocated to the nucleus and recruited the chromatin remodeler Chromodomain-helicase-DNA-binding protein 1 to enhance UBD transcription, thereby promoting endothelial barrier breakdown and monocyte infiltration. Treatment with lenalidomide (LEN), an IKZF1 inhibitor, restored claudin-5 expression, reduced MDM accumulation, and re-sensitized TMZ-resistant tumors to chemotherapy in preclinical models.
Conclusion
This study identifies a novel signaling cascade whereby TMZ-resistant GBM secretes COL6A1 to activate an IKZF1-UBD axis in ECs, disrupting blood vessel integrity and facilitating MDM infiltration. Our findings delineate the pivotal mechanism by which tumor cells engage ECs to drive MDM infiltration - a linchpin part of the positive-feedback loop that couples TMZ resistance to MDM influx. Targeting IKZF1 with LEN represents a promising strategy for restoring endothelial barrier function, reducing MDM infiltration, and enhancing chemosensitivity in GBM.
{"title":"Endothelial cells sense temozolomide resistance to facilitate monocyte-derived macrophage infiltration in glioblastoma","authors":"Wei Gao , Jianliang Huang , Kun Deng , Xiang Lin , Xinmiao Long , Xuetong Li , Meng Huang , Xiangyu Wang , Xiaoling She , Qing Liu , Minghua Wu","doi":"10.1016/j.drup.2025.101329","DOIUrl":"10.1016/j.drup.2025.101329","url":null,"abstract":"<div><h3>Aims</h3><div>Glioblastoma (GBM), particularly mesenchymal and recurrent GBM, often develops resistance to temozolomide (TMZ) and is characterized by extensive infiltration of monocyte-derived macrophages (MDM), which contributes to treatment failure. However, the mechanisms through which TMZ-resistant GBM recruits MDM remain poorly understood. This study aims to investigate the molecular drivers of MDM infiltration in the context of TMZ resistance and to identify potential therapeutic targets to disrupt this process.</div></div><div><h3>Methods</h3><div>Patient-derived GBM organoid (GBO) was utilized as a model system. We performed molecular profiling to identify genes upregulated in TMZ-resistant recurrent GBO. Endothelial cells (ECs) cultures and preclinical GBM models were used to examine disruption of tight junctions and monocyte infiltration. Mechanistic studies employed genetic knockdown, pharmacological inhibition, and assays, including Chromatin immunoprecipitation-quantitative PCR, Western blot, and immunostaining, to validate pathway activity and protein interactions.</div></div><div><h3>Results</h3><div>COL6A1 (Collagen type VI alpha 1 chain) was significantly upregulated in TMZ-resistant recurrent GBO and associated with poor survival. COL6A1 is bound to ITGB1 (Integrin beta-1) on ECs, leading to disruption of tight junctions via UBD (Ubiquitin-like modifier D)-mediated degradation of claudin-5. Furthermore, COL6A1 activated the FAK/SRC/Hippo/YAP signaling axis, which promoted lactylation of the transcription factor IKZF1 (IKAROS family zinc finger 1) at lysine 255. Lactylated IKZF1 translocated to the nucleus and recruited the chromatin remodeler Chromodomain-helicase-DNA-binding protein 1 to enhance UBD transcription, thereby promoting endothelial barrier breakdown and monocyte infiltration. Treatment with lenalidomide (LEN), an IKZF1 inhibitor, restored claudin-5 expression, reduced MDM accumulation, and re-sensitized TMZ-resistant tumors to chemotherapy in preclinical models.</div></div><div><h3>Conclusion</h3><div>This study identifies a novel signaling cascade whereby TMZ-resistant GBM secretes COL6A1 to activate an IKZF1-UBD axis in ECs, disrupting blood vessel integrity and facilitating MDM infiltration. Our findings delineate the pivotal mechanism by which tumor cells engage ECs to drive MDM infiltration - a linchpin part of the positive-feedback loop that couples TMZ resistance to MDM influx. Targeting IKZF1 with LEN represents a promising strategy for restoring endothelial barrier function, reducing MDM infiltration, and enhancing chemosensitivity in GBM.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101329"},"PeriodicalIF":21.7,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575463","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 : 2025-11-19DOI: 10.1016/j.drup.2025.101327
Rhys T. White , Craig N. Thornley , Max Bloomfield , Kristin Dyet , Juliet Elvy , Hermes Perez , Allan Hardaker , Michael Harrington , Simon Jackson , Matthew Kelly , Loushy Mangalasseril , Annette Nesdale , Xiaoyun Ren , Jenny Szeto , Claire Underwood , David Winter , Rosemary Woodhouse , Zuyu Yang
Aims
To investigate the genetic diversity in OXA-48-producing Escherichia coli ST131 in a New Zealand community outbreak, and to characterize the mobile genetic elements carrying blaOXA-48, with emphasis on the gene’s global dissemination.
Methods
Forty outbreak isolates underwent short-read sequencing; 36 also underwent long-read sequencing. Bayesian phylogenetics reconstructed the emergence and spread of the outbreak. A pangenome graph of 543 Col156 plasmids and 806 global blaOXA-48-positive contigs were analyzed to assess structural diversity, mobility, and global distribution.
Results
The outbreak clone likely emerged circa 2017, following a single introduction into New Zealand after acquiring blaOXA-48 on a 7872 bp Col156 plasmid. It shares ancestry (circa 2009) with Southeast Asian E. coli ST131 genomes. Long-read sequencing and pangenome graph analyses identified a single IS1-mediated transposition of blaOXA-48 into a Col156 plasmid backbone, observed across species and continents. Globally, blaOXA-48 is present in diverse plasmid contexts and insertion sequence arrangements and is widely distributed among Enterobacterales.
Conclusions
This is the first high-resolution genomic reconstruction of a community-associated blaOXA-48 outbreak, identifying a compact Col156 plasmid as a key vector driving carbapenem resistance. Our findings demonstrate the value of complete genome assemblies and pangenome graph analyses in resolving the structural and evolutionary dynamics of antimicrobial resistance.
目的研究新西兰社区暴发中产生oxa -48的大肠杆菌ST131的遗传多样性，并表征携带blaOXA-48的移动遗传元件，重点研究该基因的全球传播。方法对40株暴发分离株进行短读测序；36个也进行了长读测序。贝叶斯系统发育重建了疫情的出现和传播。分析了543个Col156质粒和806个全球blaoxa -48阳性contigs的全基因组图，以评估结构多样性、流动性和全球分布。结果爆发克隆可能在2017年左右出现，在7872 bp Col156质粒上获得blaOXA-48后，被引入新西兰。它与东南亚大肠杆菌ST131基因组共享祖先（大约2009年）。长读测序和全基因组图分析发现，在不同物种和大洲中都观察到is1介导的blaOXA-48转位到Col156质粒主干。在全球范围内，blaOXA-48存在于不同的质粒背景和插入序列安排中，广泛分布于肠杆菌中。这是社区相关blaOXA-48暴发的第一个高分辨率基因组重建，确定了紧凑的Col156质粒是驱动碳青霉烯类耐药性的关键载体。我们的研究结果证明了全基因组组装和泛基因组图谱分析在解决抗菌素耐药性的结构和进化动力学方面的价值。
{"title":"Integration of blaOXA-48 into a Col156 plasmid drove a carbapenem-resistant Escherichia coli ST131 outbreak in New Zealand: Global genomic evidence for the gene’s multilayered dissemination","authors":"Rhys T. White , Craig N. Thornley , Max Bloomfield , Kristin Dyet , Juliet Elvy , Hermes Perez , Allan Hardaker , Michael Harrington , Simon Jackson , Matthew Kelly , Loushy Mangalasseril , Annette Nesdale , Xiaoyun Ren , Jenny Szeto , Claire Underwood , David Winter , Rosemary Woodhouse , Zuyu Yang","doi":"10.1016/j.drup.2025.101327","DOIUrl":"10.1016/j.drup.2025.101327","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the genetic diversity in OXA-48-producing <em>Escherichia coli</em> ST131 in a New Zealand community outbreak, and to characterize the mobile genetic elements carrying <em>bla</em><sub>OXA-48</sub>, with emphasis on the gene’s global dissemination.</div></div><div><h3>Methods</h3><div>Forty outbreak isolates underwent short-read sequencing; 36 also underwent long-read sequencing. Bayesian phylogenetics reconstructed the emergence and spread of the outbreak. A pangenome graph of 543 Col156 plasmids and 806 global <em>bla</em><sub>OXA-48</sub>-positive contigs were analyzed to assess structural diversity, mobility, and global distribution.</div></div><div><h3>Results</h3><div>The outbreak clone likely emerged circa 2017, following a single introduction into New Zealand after acquiring <em>bla</em><sub>OXA-48</sub> on a 7872 bp Col156 plasmid. It shares ancestry (circa 2009) with Southeast Asian <em>E. coli</em> ST131 genomes. Long-read sequencing and pangenome graph analyses identified a single IS<em>1</em>-mediated transposition of <em>bla</em><sub>OXA-48</sub> into a Col156 plasmid backbone, observed across species and continents. Globally, <em>bla</em><sub>OXA-48</sub> is present in diverse plasmid contexts and insertion sequence arrangements and is widely distributed among Enterobacterales.</div></div><div><h3>Conclusions</h3><div>This is the first high-resolution genomic reconstruction of a community-associated <em>bla</em><sub>OXA-48</sub> outbreak, identifying a compact Col156 plasmid as a key vector driving carbapenem resistance. Our findings demonstrate the value of complete genome assemblies and pangenome graph analyses in resolving the structural and evolutionary dynamics of antimicrobial resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101327"},"PeriodicalIF":21.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559712","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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