Pub Date : 2025-12-29DOI: 10.1016/j.drup.2025.101347
Yixi Zhu , Yuyu Fang , Lijun Su , Xuebo Li , Peng Guo , Jia Duan , Kemei Ran , Na Huang , Xinyue Chen , Xiangyu Chen , Yang Liu , Zhangfeng Zhong , Chen Zhang , Jinming Zhang
Aims
Photothermal therapy shows potential for treating wound infection, but unstable agents and possible tissue damage limit its use. We aimed to develop a strategy that removes Methicillin-resistant Staphylococcus aureus (MRSA) and supports wound healing.
Methods
After confirming the stable photothermal activity of difluoroboron-curcumin (DF-Cur), we prepared a Mg2+-chelated microgel via microfluidics that co-delivers DF-Cur and glycyrrhizic acid (GA) within liposomes (termed GD Lip@Mg). And then its photothermal performance and in vitro and in vivo antibacterial ability were systematically examined. We evaluated the therapeutic efficacy of GD Lip@Mg in MRSA-infected full-thickness wounds in both rat and pig model, as well as exploring the underlying mechanisms.
Results
Proteomic analysis revealed that GA inhibits the bacterial stress-response chaperone HSP60, thereby directly sensitizing MRSA to DF-Cur-mediated photothermal killing. GD Lip@Mg plus 450 nm laser reduced bacterial counts by > 99.9 %, increased re-epithelialization, collagen deposition and vessel density, and shifted macrophages from M1 to M2 without thermal damage. Transcriptomic data associated these effects with photothermal-induced up-regulation of nerve growth factor (NGF) and down-regulation of matrix metalloproteinases (MMPs).
Conclusions
GD Lip@Mg combined with laser decreases MRSA load and promotes wound healing, providing a translatable approach for infected wounds caused by resistant bacteria.
{"title":"Difluoroboron curcumin/glycyrrhizic acid liposome-incorporated Mg²⁺-chelated microgel for MRSA-infected wound photothermal therapy","authors":"Yixi Zhu , Yuyu Fang , Lijun Su , Xuebo Li , Peng Guo , Jia Duan , Kemei Ran , Na Huang , Xinyue Chen , Xiangyu Chen , Yang Liu , Zhangfeng Zhong , Chen Zhang , Jinming Zhang","doi":"10.1016/j.drup.2025.101347","DOIUrl":"10.1016/j.drup.2025.101347","url":null,"abstract":"<div><h3>Aims</h3><div>Photothermal therapy shows potential for treating wound infection, but unstable agents and possible tissue damage limit its use. We aimed to develop a strategy that removes Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) and supports wound healing.</div></div><div><h3>Methods</h3><div>After confirming the stable photothermal activity of difluoroboron-curcumin (DF-Cur), we prepared a Mg<sup>2+</sup>-chelated microgel via microfluidics that co-delivers DF-Cur and glycyrrhizic acid (GA) within liposomes (termed GD Lip@Mg). And then its photothermal performance and <em>in vitro</em> and <em>in vivo</em> antibacterial ability were systematically examined. We evaluated the therapeutic efficacy of GD Lip@Mg in MRSA-infected full-thickness wounds in both rat and pig model, as well as exploring the underlying mechanisms.</div></div><div><h3>Results</h3><div>Proteomic analysis revealed that GA inhibits the bacterial stress-response chaperone HSP60, thereby directly sensitizing MRSA to DF-Cur-mediated photothermal killing. GD Lip@Mg plus 450 nm laser reduced bacterial counts by > 99.9 %, increased re-epithelialization, collagen deposition and vessel density, and shifted macrophages from M1 to M2 without thermal damage. Transcriptomic data associated these effects with photothermal-induced up-regulation of nerve growth factor (NGF) and down-regulation of matrix metalloproteinases (MMPs).</div></div><div><h3>Conclusions</h3><div>GD Lip@Mg combined with laser decreases MRSA load and promotes wound healing, providing a translatable approach for infected wounds caused by resistant bacteria.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101347"},"PeriodicalIF":21.7,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884495","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 : 2025-12-26DOI: 10.1016/j.drup.2025.101346
Lu Gan , Qihai Sui , Mi-die Xu , Fei Yang , Ming Li , Yitao Yuan , Yufu Lin , Xiuping Zhang , Guoshu Bi , Wei Jiang , Qun Wang , Wei Nie , Liang Liu , Fenghao Sun
Enhanced glycolysis and lactate accumulation are shared features of human cancers. Lactylation is a lactate-derived posttranslational modification. So far, the impact of lactylation on resistance to osimertinib (a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)) in patients with lung adenocarcinoma (LUAD) remains indistinct. Here, we performed 4D label-free proteomics analysis of LUAD tissues from advanced-stage EGFR-mutant patients treated with surgery with or without neoadjuvant osimertinib to reveal a global lactylation profile and explore the role and molecular mechanism of protein lactylation in resistance to osimertinib. Through scanning the lactylated proteome, we discovered that α-Enolase 1 (ENO1), which acts as a key glycolytic enzyme, underwent lactylation at lysine 89 (K89) in LUAD tissues. The levels of ENO1 lactylation were notably attenuated in LUAD tissues after effective osimertinib treatment and were notably elevated in osimertinib-resistant LUAD cells. We found that monocarboxylate transporters (MCTs) facilitated lactate uptake into LUAD cells for ENO1 lactylation primarily through a p300/CREB-binding protein C (CBP)-dependent mechanism. ENO1 facilitated metabolic reprogramming and lactate production and interacted with several key metabolic enzymes, such as pyruvate kinase M1 (PKM1), pyruvate kinase M2 (PKM2), lactate dehydrogenase B (LDHB), and malate dehydrogenase 2 (MDH2), thus forming a tumor-derived lactate/ENO1 lactylation feedback loop, eventually contributing to osimertinib resistance in LUAD. In the in vivo orthotopic xenograft osimertinib-resistant models, targeted suppression of the tumor-derived lactate/ENO1 lactylation feedback loop effectively ameliorated resistance to osimertinib. Collectively, our findings provide the basis for targeting lactate/lactate-associated signaling to combat resistance to osimertinib.
{"title":"A tumor-derived lactate/ENO1 lactylation feedback loop facilitates osimertinib resistance of lung adenocarcinoma","authors":"Lu Gan , Qihai Sui , Mi-die Xu , Fei Yang , Ming Li , Yitao Yuan , Yufu Lin , Xiuping Zhang , Guoshu Bi , Wei Jiang , Qun Wang , Wei Nie , Liang Liu , Fenghao Sun","doi":"10.1016/j.drup.2025.101346","DOIUrl":"10.1016/j.drup.2025.101346","url":null,"abstract":"<div><div>Enhanced glycolysis and lactate accumulation are shared features of human cancers. Lactylation is a lactate-derived posttranslational modification. So far, the impact of lactylation on resistance to osimertinib (a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)) in patients with lung adenocarcinoma (LUAD) remains indistinct. Here, we performed 4D label-free proteomics analysis of LUAD tissues from advanced-stage EGFR-mutant patients treated with surgery with or without neoadjuvant osimertinib to reveal a global lactylation profile and explore the role and molecular mechanism of protein lactylation in resistance to osimertinib. Through scanning the lactylated proteome, we discovered that α-Enolase 1 (ENO1), which acts as a key glycolytic enzyme, underwent lactylation at lysine 89 (K89) in LUAD tissues. The levels of ENO1 lactylation were notably attenuated in LUAD tissues after effective osimertinib treatment and were notably elevated in osimertinib-resistant LUAD cells. We found that monocarboxylate transporters (MCTs) facilitated lactate uptake into LUAD cells for ENO1 lactylation primarily through a p300/CREB-binding protein C (CBP)-dependent mechanism. ENO1 facilitated metabolic reprogramming and lactate production and interacted with several key metabolic enzymes, such as pyruvate kinase M1 (PKM1), pyruvate kinase M2 (PKM2), lactate dehydrogenase B (LDHB), and malate dehydrogenase 2 (MDH2), thus forming a tumor-derived lactate/ENO1 lactylation feedback loop, eventually contributing to osimertinib resistance in LUAD. In the <em>in vivo</em> orthotopic xenograft osimertinib-resistant models, targeted suppression of the tumor-derived lactate/ENO1 lactylation feedback loop effectively ameliorated resistance to osimertinib. Collectively, our findings provide the basis for targeting lactate/lactate-associated signaling to combat resistance to osimertinib.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101346"},"PeriodicalIF":21.7,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145845020","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 : 2025-12-24DOI: 10.1016/j.drup.2025.101345
Xiaoxiao Wang , Rangrang Fan , Geyuan Wang , Bo Han , Liangxue Zhou , Aiping Tong , Bingwen Zou , Gang Guo
Oncolytic virotherapy (OVT) has emerged as a transformative cancer treatment, leveraging tumor-selective viral replication to induce direct oncolysis and stimulate systemic antitumor immunity. Despite clinical advancements, including the FDA-approved T-VEC and subsequent agents, significant challenges remain, particularly in systemic delivery and therapeutic efficacy optimization. Intratumoral administration is largely restricted to superficial lesions, whereas intravenous delivery is hindered by rapid immune clearance due to viral antigen exposure. Additionally, insufficient antitumor efficacy presents another major hurdle, driving the growing trend of combinatorial therapies that exert synergistic effects. To overcome these barriers, nanotechnology-driven strategies, encompassing masking, targeting, and arming approaches, are revolutionizing OVT by enhancing viral stealth, improving tumor specificity, and amplifying therapeutic efficacy. Furthermore, considering biosafety concerns associated with live viral therapeutics, alternative functional nanoparticles that mimic oncolytic virus activity have been developed. These include synthetic oncolytic viruses, oncolytic peptides and polymers empowered by nanotechnology, and structurally mimetic nanoparticles. These engineered nanosystems have demonstrated potent oncolytic activity, positioning them as promising alternatives to traditional OVs while retaining their tumor-lytic functions. In this review, we explore how nanotechnology is redefining oncolytic virotherapy, focusing on masking, targeting, and arming nano-strategies. Additionally, we comprehensively examine the potential of nanoparticles to mimic and even replace oncolytic viruses, offering new avenues for enhanced cancer treatment.
{"title":"Overcoming resistance in oncolytic virotherapy: Nano-engineered solutions for systemic delivery and efficacy boost","authors":"Xiaoxiao Wang , Rangrang Fan , Geyuan Wang , Bo Han , Liangxue Zhou , Aiping Tong , Bingwen Zou , Gang Guo","doi":"10.1016/j.drup.2025.101345","DOIUrl":"10.1016/j.drup.2025.101345","url":null,"abstract":"<div><div>Oncolytic virotherapy (OVT) has emerged as a transformative cancer treatment, leveraging tumor-selective viral replication to induce direct oncolysis and stimulate systemic antitumor immunity. Despite clinical advancements, including the FDA-approved T-VEC and subsequent agents, significant challenges remain, particularly in systemic delivery and therapeutic efficacy optimization. Intratumoral administration is largely restricted to superficial lesions, whereas intravenous delivery is hindered by rapid immune clearance due to viral antigen exposure. Additionally, insufficient antitumor efficacy presents another major hurdle, driving the growing trend of combinatorial therapies that exert synergistic effects. To overcome these barriers, nanotechnology-driven strategies, encompassing masking, targeting, and arming approaches, are revolutionizing OVT by enhancing viral stealth, improving tumor specificity, and amplifying therapeutic efficacy. Furthermore, considering biosafety concerns associated with live viral therapeutics, alternative functional nanoparticles that mimic oncolytic virus activity have been developed. These include synthetic oncolytic viruses, oncolytic peptides and polymers empowered by nanotechnology, and structurally mimetic nanoparticles. These engineered nanosystems have demonstrated potent oncolytic activity, positioning them as promising alternatives to traditional OVs while retaining their tumor-lytic functions. In this review, we explore how nanotechnology is redefining oncolytic virotherapy, focusing on masking, targeting, and arming nano-strategies. Additionally, we comprehensively examine the potential of nanoparticles to mimic and even replace oncolytic viruses, offering new avenues for enhanced cancer treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101345"},"PeriodicalIF":21.7,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822700","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 : 2025-12-16DOI: 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}
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