Drug Resistance Updates最新文献

{"title":"Tumor immune organoids in immunotherapy resistance and drug screening","authors":"Minghui Zhang ,&nbsp;Lijun Li ,&nbsp;Haihong Pu ,&nbsp;Yan Wang ,&nbsp;Xiaoxin Zhang ,&nbsp;Xiaotian Guo ,&nbsp;Yanbin Zhao ,&nbsp;Qingwei Meng ,&nbsp;Mingzhu Yin","doi":"10.1016/j.drup.2026.101360","DOIUrl":"10.1016/j.drup.2026.101360","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101360"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032878","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}

{"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 ,&nbsp;Minghao Zheng ,&nbsp;Zhigang Wu ,&nbsp;Tianlei Xie ,&nbsp;Yuqin Li ,&nbsp;Ganlin Hu ,&nbsp;Shuting Fang ,&nbsp;Jing Zhang ,&nbsp;Wenli Diao ,&nbsp;Wei Zhao ,&nbsp;Hongqian Guo ,&nbsp;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":"2026-03-01","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}

{"title":"A tumor-derived lactate/ENO1 lactylation feedback loop facilitates osimertinib resistance of lung adenocarcinoma","authors":"Lu Gan ,&nbsp;Qihai Sui ,&nbsp;Mi-die Xu ,&nbsp;Fei Yang ,&nbsp;Ming Li ,&nbsp;Yitao Yuan ,&nbsp;Yufu Lin ,&nbsp;Xiuping Zhang ,&nbsp;Guoshu Bi ,&nbsp;Wei Jiang ,&nbsp;Qun Wang ,&nbsp;Wei Nie ,&nbsp;Liang Liu ,&nbsp;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":"2026-03-01","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}

{"title":"RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation","authors":"Mengyuan Wu ,&nbsp;Xu Huang ,&nbsp;Miao Lin ,&nbsp;Zhiyun Duan ,&nbsp;Zitao Jian ,&nbsp;Runze You ,&nbsp;Peiyi Xie ,&nbsp;Zhiwei Wu ,&nbsp;Siyun Lin ,&nbsp;Shaoyuan Zhang ,&nbsp;Wenyi Xu ,&nbsp;Heng Jiao ,&nbsp;Han Tang ,&nbsp;Lei Guo ,&nbsp;Hao Wang ,&nbsp;Weigang Guo ,&nbsp;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}

{"title":"Myeloid immune checkpoint blockade overcomes antibiotic resistance in bone infection by enhancing efferocytosis and suppressing MSC PANoptosis","authors":"Yudun Qu ,&nbsp;Shuanji Ou ,&nbsp;Jianping Wen ,&nbsp;Jiaxuan Li ,&nbsp;Changliang Xia ,&nbsp;Pengchen Chen ,&nbsp;Yang Yang ,&nbsp;Jiabao Liu ,&nbsp;Wenjun Li ,&nbsp;Rongshen Yang ,&nbsp;Wei Zen ,&nbsp;Tingyu He ,&nbsp;Jiatao Lei ,&nbsp;Wei Zhang ,&nbsp;Yunfei Ma ,&nbsp;Nan Jiang ,&nbsp;Yong Qi ,&nbsp;Changpeng Xu","doi":"10.1016/j.drup.2025.101348","DOIUrl":"10.1016/j.drup.2025.101348","url":null,"abstract":"<div><div>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 <em>in vivo</em> and <em>in vitro</em> 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.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101348"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884496","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}

{"title":"Deciphering the roles of AcrAB-TolC efflux pump in promoting the transmission of antibiotic resistance","authors":"Shuyao Zhu ,&nbsp;Feiyu Yu ,&nbsp;Bingqing Yang ,&nbsp;Miao Zhang ,&nbsp;Haijie Zhang ,&nbsp;Zhiqiang Wang ,&nbsp;Yuan Liu","doi":"10.1016/j.drup.2026.101358","DOIUrl":"10.1016/j.drup.2026.101358","url":null,"abstract":"<div><div>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 <em>acrA</em>, <em>acrB</em> or <em>tolC</em> significantly reduce plasmid transfer, and complementation fully restores conjugative frequencies to control levels. Mechanistic investigations reveal that <em>acrB</em> 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 <em>in vivo</em> and <em>in vitro</em>. 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.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101358"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000949","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}

{"title":"Glucocorticoid receptor activated by dexamethasone promotes the chemoresistance and stemness of lung cancer","authors":"Ting Yu ,&nbsp;Dandan Peng ,&nbsp;Xiao Liang ,&nbsp;Wen Nie ,&nbsp;Huaicheng Tan ,&nbsp;Siyuan Chen ,&nbsp;Huashan Shi ,&nbsp;Yuquan Wei ,&nbsp;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":"2026-03-01","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}

{"title":"Linc01833 drives gemcitabine resistance in non-small cell lung cancer by shielding SLC7A11 from WWP1-mediated ubiquitination and inhibiting ferroptosis","authors":"Lianli Ni ,&nbsp;Hailong Li ,&nbsp;Peipei Chen ,&nbsp;Yun Yu ,&nbsp;Chenjun Xie ,&nbsp;Wenfeng Hong ,&nbsp;Gaowei Fang ,&nbsp;Baohong Wan ,&nbsp;Yiwei Shen ,&nbsp;Peng Zou ,&nbsp;Wangyu Zhu ,&nbsp;Zhiguo Liu ,&nbsp;Xiaokun Li ,&nbsp;Ri Cui","doi":"10.1016/j.drup.2026.101351","DOIUrl":"10.1016/j.drup.2026.101351","url":null,"abstract":"<div><div>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 <em>in vivo</em> and <em>in vitro</em>. 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.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101351"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895425","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}

{"title":"DEAF1 confers resistance to adriamycin-induced apoptosis and pyroptosis in multiple myeloma","authors":"Zhendong Deng ,&nbsp;Yongxin Wei ,&nbsp;Shuang Liu ,&nbsp;Lu Chen ,&nbsp;Xuhui Wang ,&nbsp;Zihao Liu ,&nbsp;Lingling Liu ,&nbsp;Yaohui Wang ,&nbsp;Xinyu Lv ,&nbsp;Shanliang Sun ,&nbsp;Haiwen Ni ,&nbsp;Chunyan Gu ,&nbsp;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":"2026-03-01","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}

{"title":"Difluoroboron curcumin/glycyrrhizic acid liposome-incorporated Mg²⁺-chelated microgel for MRSA-infected wound photothermal therapy","authors":"Yixi Zhu ,&nbsp;Yuyu Fang ,&nbsp;Lijun Su ,&nbsp;Xuebo Li ,&nbsp;Peng Guo ,&nbsp;Jia Duan ,&nbsp;Kemei Ran ,&nbsp;Na Huang ,&nbsp;Xinyue Chen ,&nbsp;Xiangyu Chen ,&nbsp;Yang Liu ,&nbsp;Zhangfeng Zhong ,&nbsp;Chen Zhang ,&nbsp;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 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 <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 &gt; 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":"2026-03-01","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}