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Tumor immune organoids in immunotherapy resistance and drug screening 肿瘤免疫类器官在免疫治疗中的耐药性和药物筛选

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI: 10.1016/j.drup.2026.101360

Minghui Zhang , Lijun Li , Haihong Pu , Yan Wang , Xiaoxin Zhang , Xiaotian Guo , Yanbin Zhao , Qingwei Meng , Mingzhu Yin

Tumor organoids represent a transformative tool in cancer research, as they retain the genetic and phenotypic features of parental tumors and accurately recapitulate their heterogeneity. However, one of the limitations of tumor organoids lies in the lack of immune and stromal cells in the tumor microenvironment (TME). To address this challenge, tumor immune organoids have been developed, which contain complex immune and stromal compartments beyond preserving tumor architecture. Tumor immune organoids show great potential for studying personalized immunotherapy responses and mechanisms of immunotherapy resistance. However, integrating the models into clinical practice remains challenging. In this Review, we outline currently available and rapidly evolving tumor immune organoids that recapitulate the TME and immunotherapy effects. These tumor immune organoids can be established by co-culturing traditional tumor organoids with stromal and immune cells, as well as preserving the TME using microfluidic and air-liquid interface (ALI) culture technologies. Additionally, we delineate the applications of tumor immune organoids for unravelling tumor-intrinsic and -extrinsic immunotherapy resistance mechanisms, predicting immunotherapy efficacy, and facilitating novel drug screening. Finally, we highlight the current challenges of organoid culture technology that need to be addressed for its broader applications, both in basic and translational cancer research. This review provides a theoretical foundation for future research on the application of tumor immune organoids to investigate immunotherapy resistance mechanisms and develop personalized immunotherapies. With continuous advancements, tumor immune organoids are expected to play an increasingly indispensable role in cancer immunotherapy, providing patients with more effective and tailored treatment options.

肿瘤类器官是癌症研究中的一种变革性工具，因为它们保留了亲代肿瘤的遗传和表型特征，并准确地概括了它们的异质性。然而，肿瘤类器官的局限性之一在于肿瘤微环境（TME）中缺乏免疫细胞和基质细胞。为了应对这一挑战，肿瘤免疫类器官已经被开发出来，它包含复杂的免疫和间质室，而不仅仅是保存肿瘤结构。肿瘤免疫类器官在研究个体化免疫治疗反应和免疫治疗耐药机制方面具有很大的潜力。然而，将这些模型整合到临床实践中仍然具有挑战性。在这篇综述中，我们概述了目前可用的和快速发展的肿瘤免疫类器官，概述了TME和免疫治疗的效果。这些肿瘤免疫类器官可以通过传统的肿瘤类器官与基质细胞和免疫细胞共培养，以及利用微流体和气液界面（ALI）培养技术保存TME来建立。此外，我们描述了肿瘤免疫类器官在揭示肿瘤内在和外在免疫治疗耐药机制、预测免疫治疗疗效和促进新药筛选方面的应用。最后，我们强调了类器官培养技术目前面临的挑战，这些挑战需要在基础和转化癌症研究中得到更广泛的应用。本文综述为今后应用肿瘤免疫类器官研究免疫治疗耐药机制、开发个性化免疫治疗提供理论基础。随着技术的不断进步，肿瘤免疫类器官有望在癌症免疫治疗中发挥越来越重要的作用，为患者提供更有效、更有针对性的治疗选择。

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引用次数: 0

Entinostat overcomes cisplatin resistance in bladder cancer by promoting H3K18la-mediated DHRS2 expression and nuclear translocation to suppress the AKR1C3-androgen axis 恩替诺他通过促进h3k18la介导的DHRS2表达和核易位抑制akr1c3 -雄激素轴来克服膀胱癌的顺铂耐药

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-12-09 DOI: 10.1016/j.drup.2025.101343

Guanghui Xu , Minghao Zheng , Zhigang Wu , Tianlei Xie , Yuqin Li , Ganlin Hu , Shuting Fang , Jing Zhang , Wenli Diao , Wei Zhao , Hongqian Guo , Junlong Zhuang

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.

表观遗传失调是膀胱癌（BCa）患者顺铂耐药的重要因素。越来越多的研究表明顺铂和恩替诺他具有协同作用，恩替诺他是fda批准的组蛋白去乙酰化酶（HDAC）抑制剂，然而，这种作用的潜在机制尚不清楚。本研究证实了顺铂和恩替诺他在BCa细胞中的协同作用。综合RNA-seq和ATAC-seq分析显示，顺铂和恩替诺他联合治疗方案导致铂耐药和DNA损伤修复相关通路的显著下调。我们重点研究候选基因脱氢酶/还原酶成员2 (DHRS2)，发现恩替诺他通过促进组蛋白H3K18乳酸化（H3K18la）介导的DHRS2上调和增强DHRS2的核易位来对抗顺铂耐药。DHRS2下调通过上调醛酮还原酶家族1成员C3 （AKR1C3）促进顺铂耐药，AKR1C3是雄激素合成的关键酶。此外，我们验证了临床BCa样本中DHRS2水平与AKR1C3表达之间的负相关。研究发现，高DHRS2和低AKR1C3表达与改善新辅助化疗（NAC）反应相关。此外，高DHRS2特异性地预测男性患者更好的生存率，表明性别特异性雄激素参与。总的来说，这些发现阐明了恩替诺他顺铂致敏作用的表观遗传机制，并确定了dhrs2 - akr1c3雄激素轴是一个潜在的靶点，特别是对于男性患者。

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引用次数: 0

A tumor-derived lactate/ENO1 lactylation feedback loop facilitates osimertinib resistance of lung adenocarcinoma 肿瘤源性乳酸/ en1乳酸化反馈回路促进肺腺癌对奥希替尼的耐药

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-12-26 DOI: 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.

糖酵解和乳酸积累增强是人类癌症的共同特征。乳酸化是一种由乳酸衍生的翻译后修饰。到目前为止，乳酸化对肺腺癌（LUAD）患者对奥希替尼（第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI））耐药的影响尚不清楚。在这里，我们对接受或不接受新辅助奥希替尼手术治疗的晚期egfr突变患者的LUAD组织进行了4D无标记蛋白质组学分析，以揭示全局的乳酸化特征，并探讨蛋白质乳酸化在奥希替尼耐药中的作用和分子机制。通过扫描乳酸化蛋白组，我们发现LUAD组织中作为关键糖酵解酶的α-烯醇化酶1 （ENO1）在赖氨酸89 （K89）处发生了乳酸化。在有效的奥希替尼治疗后，LUAD组织中ENO1乳酸化水平显著降低，而在奥希替尼耐药的LUAD细胞中ENO1乳酸化水平显著升高。我们发现单羧酸转运体（mct）主要通过p300/ creb结合蛋白C （CBP）依赖机制促进乳酸摄取到LUAD细胞中进行ENO1的乳酸化。ENO1促进代谢重编程和乳酸生成，并与几种关键代谢酶如丙酮酸激酶M1 （PKM1）、丙酮酸激酶M2 （PKM2）、乳酸脱氢酶B （LDHB）和苹果酸脱氢酶2 （MDH2）相互作用，从而形成肿瘤源性乳酸/ENO1乳酸化反馈回路，最终导致LUAD患者对奥希替尼耐药。在体内原位异种移植物奥西替尼耐药模型中，靶向抑制肿瘤来源的乳酸/ENO1乳酸化反馈回路有效地改善了对奥西替尼的耐药。总的来说，我们的研究结果为靶向乳酸/乳酸相关信号来对抗对奥希替尼的耐药性提供了基础。

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引用次数: 0

RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation RCN2通过ubr5介导的PPP2CA泛素化和降解促进食管鳞癌转移和顺铂耐药

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-12-04 DOI: 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.

转移进展和治疗耐药性决定了食管鳞状细胞癌（ESCC）患者预后不良的结果，强调了迫切需要了解其背后的分子机制。网状定位蛋白2 （Reticulocalbin 2, RCN2）是一种定位于内质网管腔的钙结合蛋白，在多种癌症类型中介导肿瘤进展。然而，RCN2在ESCC中的作用仍未被探索。方法体外和体内观察RCN2对ESCC进展、转移及顺铂耐药的影响。通过RNA-seq、TMT 10X质谱分析、LC-MS/MS分析筛选与RCN2相关的下游调控机制，并通过Western blot、免疫沉淀、免疫荧光、GST pull-down实验和救援实验进一步验证。结果我们在ESCC转移患者的肿瘤组织中观察到RCN2高表达，这与转移风险高和生存期差相关。蛋白磷酸酶2 a （PP2A）的催化亚基PPP2CA和泛素蛋白连接酶E3组分n -识别蛋白5 （UBR5）被确定为新的RCN2功能相互作用物。机制上，RCN2促进PPP2CA泛素化和降解依赖于UBR5的HECT结构域，从而激活PI3K-AKT信号通路。此外，激活的RCN2-PPP2CA-PI3K-AKT轴在ESCC临床标本中得到验证。最后，在皮下和肺转移模型中，靶向抑制RCN2与CDDP治疗协同抑制肿瘤生长和转移。总之，这些发现表明RCN2是ESCC转移和CDDP耐药的新驱动因素。RCN2可能是ESCC的一个有希望的治疗靶点。

{"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":"2026-03-01","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}

引用次数: 0

Myeloid immune checkpoint blockade overcomes antibiotic resistance in bone infection by enhancing efferocytosis and suppressing MSC PANoptosis 髓系免疫检查点阻断通过增强胞浆功能和抑制骨髓间充质干细胞泛凋亡来克服骨感染中的抗生素耐药性

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-12-29 DOI: 10.1016/j.drup.2025.101348

Yudun Qu , Shuanji Ou , Jianping Wen , Jiaxuan Li , Changliang Xia , Pengchen Chen , Yang Yang , Jiabao Liu , Wenjun Li , Rongshen Yang , Wei Zen , Tingyu He , Jiatao Lei , Wei Zhang , Yunfei Ma , Nan Jiang , Yong Qi , Changpeng Xu

Antibiotic resistance in bone infection remains a major clinical challenge, leading to persistent inflammation, fibrotic remodeling, and failure of bone regeneration. Emerging evidence suggests that dysregulated immune–stromal interactions play a pivotal role in this process; however, how antibiotic resistance disrupts the osteoimmune balance—particularly the crosstalk between macrophages and mesenchymal stem cells (MSCs)—remains unclear. Here, we integrated single-cell RNA sequencing (scRNA-seq) of peri-infectious bone tissue with in vivo and in vitro experiments to delineate the cellular and molecular mechanisms underlying osteoimmune alterations associated with antibiotic resistance. Analysis of 101,336 single cells identified 10 major cell types, including macrophages, mesenchymal stem cells (MSCs), and neutrophils. Resistant infection induced M1-polarized macrophages with defective efferocytosis and MSCs undergoing PANoptosis and impaired osteogenic differentiation. Ligand–receptor analysis highlighted the SIRPα–Thbs1–CD47 axis as a key mediator of dysfunctional macrophage–MSC communication. Functional inhibition of CD47 signaling restored efferocytosis, mitigated antibiotic resistance–associated inflammation, and promoted bone regeneration. Collectively, these findings define a macrophage checkpoint–mediated mechanism linking immune dysregulation to osteogenic failure in antibiotic-resistant bone infection and suggest that targeting this axis may offer a promising therapeutic strategy.

骨感染的抗生素耐药性仍然是一个主要的临床挑战，导致持续炎症，纤维化重塑和骨再生失败。新出现的证据表明，失调的免疫基质相互作用在这一过程中起着关键作用；然而，抗生素耐药性如何破坏骨免疫平衡——特别是巨噬细胞和间充质干细胞（MSCs）之间的串扰——仍不清楚。在这里，我们将感染周围骨组织的单细胞RNA测序（scRNA-seq）与体内和体外实验相结合，以描述与抗生素耐药性相关的骨免疫改变的细胞和分子机制。对101336个单细胞的分析确定了10种主要的细胞类型，包括巨噬细胞、间充质干细胞（MSCs）和中性粒细胞。耐药感染诱导m1极化巨噬细胞产生有缺陷的efferocytosis和MSCs发生PANoptosis和成骨分化受损。配体受体分析强调SIRPα-Thbs1-CD47轴是巨噬细胞- msc通讯功能失调的关键介质。CD47信号的功能抑制恢复了efferocytosis，减轻了抗生素耐药性相关的炎症，并促进了骨再生。总的来说，这些发现定义了巨噬细胞检查点介导的机制，将免疫失调与抗生素耐药骨感染中的成骨衰竭联系起来，并表明靶向这一轴可能提供一种有希望的治疗策略。

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引用次数: 0

Deciphering the roles of AcrAB-TolC efflux pump in promoting the transmission of antibiotic resistance 解读acrabb - tolc外排泵在促进抗生素耐药性传播中的作用

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2026-01-19 DOI: 10.1016/j.drup.2026.101358

Shuyao Zhu , Feiyu Yu , Bingqing Yang , Miao Zhang , Haijie Zhang , Zhiqiang Wang , Yuan Liu

Plasmid-mediated conjugative transfer drives the global dissemination of antimicrobial resistance, posing a global threat to public health. Besides extruding antibiotics, bacterial multidrug efflux pumps modulate virulence, yet their influence on resistance plasmid spread in antibiotic-free settings remains undefined. Herein, we demonstrate that the AcrAB-TolC efflux pump is critical for the horizontal transfer of model plasmid RP4–7 and diverse clinical resistance plasmids. Single deletions of acrA, acrB or tolC significantly reduce plasmid transfer, and complementation fully restores conjugative frequencies to control levels. Mechanistic investigations reveal that acrB deficiency reduces interbacterial contact, diminishes energy metabolism, and impairs activity of the glutamate decarboxylase, quorum sensing and the conjugative systems. Furthermore, we identify chlorpromazine as a potential AcrB ligand, which blocks plasmid transfer both in vivo and in vitro. Collectively, our findings reveal the role of efflux pumps in plasmid transfer and underscore AcrB as a druggable target to curtail the spread of antibiotic resistance.

质粒介导的结合转移推动了抗菌素耐药性的全球传播，对公共卫生构成全球性威胁。除了挤出抗生素外，细菌多药外排泵还调节毒力，但它们对无抗生素环境中耐药质粒传播的影响仍不清楚。在此，我们证明acrabb - tolc外排泵对于模型质粒RP4-7和各种临床耐药质粒的水平转移至关重要。acrA， acrB或tolC的单个缺失显著减少质粒转移，并且互补完全恢复共轭频率到控制水平。机制研究表明，acrB缺乏减少了细菌间的接触，减少了能量代谢，损害了谷氨酸脱羧酶、群体感应和共轭系统的活性。此外，我们发现氯丙嗪是一种潜在的AcrB配体，可以在体内和体外阻断质粒转移。总的来说，我们的研究结果揭示了外排泵在质粒转移中的作用，并强调AcrB是一种可抑制抗生素耐药性传播的药物靶点。

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引用次数: 0

Glucocorticoid receptor activated by dexamethasone promotes the chemoresistance and stemness of lung cancer 地塞米松激活糖皮质激素受体促进肺癌的化疗耐药和干细胞

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-11-25 DOI: 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.

目的糖皮质激素（GCs）如地塞米松通常用于减轻化疗药物的副作用或晚期癌症引起的症状。然而，越来越多的证据发现糖皮质激素在实体肿瘤中诱导化疗耐药，但其潜在影响和潜在机制尚不清楚。本研究旨在揭示糖皮质激素诱导肺癌化疗耐药的潜在机制。方法采用体外和体内试验，观察地塞米松对化疗疗效和干细胞特性的影响。通过western blot、蛋白免疫沉淀、分子动力学模拟、高分辨率质谱检测和rna测序等方法揭示地塞米松作用机制。通过对公共数据集的转录组学分析，评估肺癌患者糖皮质激素受体（GR）激活的预后价值。结果地塞米松预处理能显著抑制多种化疗药物介导的肺癌细胞凋亡。肺转移小鼠模型显示，地塞米松预处理明显降低紫杉醇的抗肿瘤效果。地塞米松治疗后，肺癌干细胞相关特性明显改善，表现为自我更新能力增强，化疗耐药改善，体内肿瘤启动电位增加。此外，我们发现地塞米松诱导的化学耐药和干性特性依赖于gr介导的β-连环蛋白核易位。GR的n端结构域（NTD）和激活功能2 （AF2）区域介导了与β-catenin相互作用的主要贡献。来自TCGA-LUAD和GEO数据集的临床样本分析表明，GR激活与肺癌患者更差的生存率和更少的化疗获益相关。结论地塞米松通过诱导GR/β-catenin复合物核易位，促进肺癌化疗耐药和干细胞的发生。从长远来看，在化疗期间给患者开糖皮质激素时需要更多的注意。

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引用次数: 0

Linc01833 drives gemcitabine resistance in non-small cell lung cancer by shielding SLC7A11 from WWP1-mediated ubiquitination and inhibiting ferroptosis Linc01833通过屏蔽SLC7A11免受wwp1介导的泛素化和抑制铁凋亡，驱动非小细胞肺癌的吉西他滨耐药

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2026-01-02 DOI: 10.1016/j.drup.2026.101351

Lianli Ni , Hailong Li , Peipei Chen , Yun Yu , Chenjun Xie , Wenfeng Hong , Gaowei Fang , Baohong Wan , Yiwei Shen , Peng Zou , Wangyu Zhu , Zhiguo Liu , Xiaokun Li , Ri Cui

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and the leading cause of cancer-related deaths globally. The RNA binding protein Quaking-5 (QKI-5) has been established as a tumor suppressor in NSCLC. Inducing ferroptosis is regarded as an effective therapeutic strategy for cancer treatment, and long non-coding RNA (lncRNA) plays a critical role in the regulation of ferroptosis. However, the relationship between QKI-5-regulated lncRNA and ferroptosis remains uncharacterized in NSCLC. In this study, we discovered that QKI-5 downregulates the oncogenic lncRNA linc01833, which inhibits ferroptosis and promotes NSCLC progression by activating SLC7A11/GPX4 signaling pathway. Mechanistically, QKI-5 negatively regulates the stability of linc01833, leading to increased linc01833 expression in NSCLC. Silencing linc01833 enhanced WW domain-containing E3 ubiquitin protein ligase 1 (WWP1)-mediated ubiquitination of SLC7A11, resulting in decreased SLC7A11 expression, while overexpression of linc01833 produced the opposite effect. Further analyses demonstrated that linc01833 diminished the anti-tumor effect of gemcitabine (GEM) in NSCLC both in vivo and in vitro. Additionally, knocking down linc01833 or SLC7A11 is able to inhibit GEM resistant NSCLC growth. Our findings suggest that targeting linc01833 to induce ferroptosis could enhance the cytotoxic effects of chemotherapeutic agents and may serve as an effective therapeutic strategy for some NSCLC patients.

非小细胞肺癌（NSCLC）是最常见的肺癌形式，也是全球癌症相关死亡的主要原因。RNA结合蛋白Quaking-5 （QKI-5）已被确定为非小细胞肺癌的肿瘤抑制因子。诱导铁下垂被认为是一种有效的癌症治疗策略，而长链非编码RNA （long non-coding RNA, lncRNA）在铁下垂的调控中起着关键作用。然而，在非小细胞肺癌中，qki -5调控的lncRNA与铁下垂的关系尚不明确。在本研究中，我们发现QKI-5下调致癌lncRNA linc01833，通过激活SLC7A11/GPX4信号通路抑制铁下垂，促进NSCLC进展。在机制上，QKI-5负调控linc01833的稳定性，导致linc01833在NSCLC中的表达增加。沉默linc01833增强了含WW结构域E3泛素蛋白连接酶1 （WWP1）介导的SLC7A11泛素化，导致SLC7A11表达降低，而过表达linc01833则产生相反的效果。进一步的分析表明，linc01833在体内和体外均降低了吉西他滨（GEM）在NSCLC中的抗肿瘤作用。此外，敲除linc01833或SLC7A11能够抑制GEM抗性NSCLC的生长。我们的研究结果表明，靶向linc01833诱导铁凋亡可以增强化疗药物的细胞毒性作用，可能成为一些非小细胞肺癌患者的有效治疗策略。

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引用次数: 0

DEAF1 confers resistance to adriamycin-induced apoptosis and pyroptosis in multiple myeloma DEAF1对阿霉素诱导的多发性骨髓瘤细胞凋亡和焦亡具有抗性

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-12-16 DOI: 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.

异常转录因子（TFs）介导的转录失调是耐药的关键驱动因素。多发性骨髓瘤（MM）的一线治疗后，阿霉素耐药性（ADR）经常出现。本研究旨在鉴定与MM耐ADR相关的新型tf，并阐明其潜在机制。方法采用fitc标记的celastrol蛋白芯片检测，鉴定变形表皮自调节因子1 （DEAF1）为MM的潜在靶点，并采用高通量测序方法鉴定DEAF1的下游靶点。利用体内和体外模型来描述DEAF1在MM细胞增殖和ADR抗性中的作用。结果耳聋1高表达与MM患者预后不良相关，并可促进MM细胞增殖，诱导ADR耐药。从机制上讲，DEAF1通过其SAND结构域直接与RAD50启动子结合，上调RAD50的表达，从而激活ATM通路。此外，DEAF1通过MYND结构域募集ap -2- α (AP-2α)，导致酪氨酸蛋白激酶Fer （Fer）下调。这种下调破坏了ferr介导的GSDME磷酸化，而已知这可以提高caspase-3对GSDME的切割效率。此外，celastrol与ADR协同作用，通过破坏DEAF1与其靶基因启动子的结合来抑制MM细胞的活力。结论研究结果表明，DEAF1通过增强DNA损伤修复和抑制GSDME轴的裂解，从而减弱adr诱导的MM细胞凋亡和焦亡。本研究为MM的治疗提供了新的治疗靶点。

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引用次数: 0

Difluoroboron curcumin/glycyrrhizic acid liposome-incorporated Mg²⁺-chelated microgel for MRSA-infected wound photothermal therapy 二氟硼姜黄素/甘草酸脂质体结合Mg 2 +螯合微凝胶用于mrsa感染创面光热治疗

IF 21.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2026-03-01 Epub Date: 2025-12-29 DOI: 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.

目的光热疗法显示出治疗伤口感染的潜力，但不稳定的药物和可能的组织损伤限制了它的应用。我们的目标是开发一种去除耐甲氧西林金黄色葡萄球菌（MRSA）并支持伤口愈合的策略。方法在确认了二氟硼姜黄素（DF-Cur）稳定的光热活性后，我们通过微流体制备了一种Mg2+螯合微凝胶，该微凝胶在脂质体（GD Lip@Mg）中共同递送DF-Cur和甘草酸（GA）。并对其光热性能和体外、体内抗菌能力进行了系统检测。我们评估了GD Lip@Mg对mrsa感染的大鼠和猪全层伤口模型的治疗效果，并探讨了其潜在机制。结果蛋白质组学分析显示，GA抑制细菌应激反应伴侣HSP60，从而直接使MRSA对df - cu介导的光热杀伤敏感。GD Lip@Mg + 450 nm激光使细菌计数减少>； 99.9 %，增加再上皮化，胶原沉积和血管密度，并使巨噬细胞从M1向M2转移而无热损伤。转录组学数据将这些效应与光热诱导的神经生长因子（NGF）上调和基质金属蛋白酶（MMPs）下调联系起来。结论sgd Lip@Mg联合激光可降低MRSA负荷，促进创面愈合，为耐药菌感染创面提供了一种可翻译的方法。

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引用次数: 0