Drug Resistance Updates最新文献

{"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":"2026-01-19","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":"Novel quinoxaline-based survivin degraders overcome docetaxel-resistance in castration-resistant prostate cancer","authors":"Caoqinglong Huang ,&nbsp;Xunzhen Zheng ,&nbsp;Qingbin Cui ,&nbsp;Robert C. Peery ,&nbsp;Zizheng Dong ,&nbsp;Xiaohong Li ,&nbsp;Jing-Yuan Liu ,&nbsp;Jian-Ting Zhang","doi":"10.1016/j.drup.2026.101356","DOIUrl":"10.1016/j.drup.2026.101356","url":null,"abstract":"<div><div>Survivin, a homodimeric protein in the Inhibitor of Apoptosis Protein (IAP) family, plays a dual role in apoptosis inhibition and cell cycle regulation. Overexpressed in many cancers but absent in most adult tissues, survivin is a compelling therapeutic target linked to disease progression, aggressiveness, and drug resistance. However, its structural properties render it “undruggable” by conventional approaches. Here, we present a transformative strategy to overcome this challenge by targeting survivin’s hydrophobic dimerization interface, inducing proteasome-dependent degradation. Building on the initial discovery of the survivin degrader LQZ-7I, we developed optimized analogs with significantly enhanced potency through medicinal chemistry. Our top-performing compounds, 7I10 and 7I14, selectively disrupt survivin dimerization, leading to its degradation and spontaneous apoptosis in castration-resistant prostate cancer (CRPC) cells. We also showed that survivin contributes to acquired resistance to docetaxel, the frontline chemotherapy for metastatic CRPC, and that the survivin degraders exhibit potent synergy with docetaxel, and the combination of 7I14 and docetaxel synergistically eliminates CRPC xenografts without added toxicity. This work introduces a first-in-class therapeutic approach that overcomes long-standing barriers to drugging survivin, offering a new avenue for combating docetaxel-resistant metastatic CRPC. With robust efficacy, a favorable safety profile, and potential for clinical translation, 7I10 and 7I14 represent significant advancements in the development of targeted cancer therapies to overcome docetaxel resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101356"},"PeriodicalIF":21.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956675","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":"The hallmarks of oncogenic signaling: From pathways to resistance in cancer therapy","authors":"Muhammad Tufail ,&nbsp;Kunxiang Gong ,&nbsp;Bushra Ijaz ,&nbsp;Harsh Patel ,&nbsp;Weng-Onn Lui ,&nbsp;Xiumei Wang ,&nbsp;Jie Li","doi":"10.1016/j.drup.2026.101355","DOIUrl":"10.1016/j.drup.2026.101355","url":null,"abstract":"<div><div>Oncogenic signal transduction pathways play pivotal roles in tumor progression by regulating essential cellular processes such as proliferation, survival, angiogenesis, invasion, and immune evasion. These pathways are frequently deregulated in cancer due to genetic mutations, epigenetic modifications, or microenvironmental influences. These genetic or epigenetics shifts enable cancer cells to bypass growth suppressors, resist apoptosis, and sustain uncontrolled growth. While targeted therapies have shown promise in inhibiting these signaling cascades, therapeutic resistance and tumor heterogeneity remain major obstacles. To address these limitations, emerging strategies, including combination therapies, next-generation kinase inhibitors, and immunomodulatory approaches, are being developed to overcome these challenges. This review explores the molecular mechanisms underlying oncogenic pathway activation, their contributions to hallmark cancer traits and resistance, and therapeutic advancements targeting these pathways. By understanding these signaling networks, we aim to highlight opportunities for improving cancer treatment and addressing therapeutic resistance in the evolving landscape of oncology.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101355"},"PeriodicalIF":21.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956676","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":"Single-cell transcriptome analysis of patient-derived organoids captures inter- and intratumor heterogeneity and uncovers targetable pathways in high grade serous ovarian cancer","authors":"Marco Pieraccioli ,&nbsp;Alessandra Ciucci ,&nbsp;Christian Corti ,&nbsp;Roberta Mastrantonio ,&nbsp;Eleonora Kristina Scarpone ,&nbsp;Eleonora Cesari ,&nbsp;Alessia Piermattei ,&nbsp;Angelo Minucci ,&nbsp;Andrea Urbani ,&nbsp;Floriana Camarda ,&nbsp;Anna Fagotti ,&nbsp;Luca Tamagnone ,&nbsp;Giovanni Scambia ,&nbsp;Camilla Nero ,&nbsp;Claudio Sette","doi":"10.1016/j.drup.2026.101354","DOIUrl":"10.1016/j.drup.2026.101354","url":null,"abstract":"<div><h3>Aim</h3><div>High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer. HGSOC is characterized by high inter- and intra-tumoral heterogeneity, which contributes to chemotherapy resistance. Patient-derived organoids (PDOs) are valuable preclinical models to elucidate the biology of human cancers and to test their response to treatments. This study aims at characterizing the cellular heterogeneity of PDOs and to uncover vulnerabilities of chemotherapy resistant HGSOC.</div></div><div><h3>Methods</h3><div>Single-cell transcriptomics of PDOs developed from biopsies of platinum-resistant and platinum-sensitive HGSOC. Chemotherapeutic treatments of HGSOC PDOs and of ascitic-derived ovarian cancer cells and immunohistochemistry analyses of tissues from independent HGSOC patients.</div></div><div><h3>Results</h3><div>HGSOC PDOs comprise subclusters of cells exhibiting different transcriptional states and patient-specific signatures. Proliferative and non-proliferative subclusters co-exist in PDOs and their relative proportion is altered by chemotherapy. Proliferative cell sub-populations exhibit expression of cell cycle and DNA damage response related genes, whereas non-proliferative sub-populations display inflammatory signatures. Furthermore, sensitivity to platinum-based treatments was inversely correlated with oxidative phosphorylation (OXHPOS) in PDOs, indicating a metabolic switch associated with chemoresistance. Accordingly, platinum-resistant PDOs and ascitic HGSOC cells show higher sensitivity to OXHPOS inhibition. We found that neoadjuvant chemotherapy (NACT) directly up-regulates oncogenic and metabolic pathways that are involved in development of recurrence, such as the <em>MYC</em> and OXPHOS genes. NACT also induces the expression of major histocompatibility complex type II (MHC-II) molecules. Immunohistochemistry confirmed MHC-II up-regulation in post-NACT biopsies, indicating that tumour cells mount a general antigen-presenting response upon chemotherapy, associated with recruitment of infiltrating immune cells.</div></div><div><h3>Conclusion</h3><div>PDOs maintain the inter- and intra-tumoral cellular heterogeneity of HGSOC. Chemotherapy targets proliferative cell subclusters, sparing non-proliferative ones. Dependency on OXPHOS represents an actionable vulnerability in PDOs, which can be exploited to hijack chemoresistance. Sequential chemotherapy and immunotherapy may also improve clinical response of HGSOC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101354"},"PeriodicalIF":21.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925904","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":"Mechanisms of resistance to antibody-drug conjugates in breast cancer","authors":"Baris Cerci ,&nbsp;Ozge Saatci ,&nbsp;Mark Basik ,&nbsp;Ozgur Sahin","doi":"10.1016/j.drup.2026.101353","DOIUrl":"10.1016/j.drup.2026.101353","url":null,"abstract":"<div><div>Antibody-drug conjugate (ADC) is a drug modality where a payload is conjugated to an antibody for its targeted delivery to the cancer cells. In breast cancer, the treatment landscape has changed remarkably in the past decade by the introduction of several effective ADCs in the clinic. However, intrinsic (de novo) or acquired resistance to these treatments is a major obstacle. In this review, we summarize the role of target antigen alterations, cell-intrinsic mechanisms that overcome payload cytotoxicity, and the pro-tumorigenic tumor microenvironment (TME) as the major drivers of resistance to ADCs. Furthermore, we discuss how different mechanisms of ADC resistance are integrated and highlight the most clinically relevant ones. We then provide the current and emerging strategies, such as biomarker-guided drug combinations and novel ADC designs to overcome resistance to ADCs. Finally, we provide future perspectives on the use of preclinical models that better reflect both intratumor heterogeneity and TME, integration of exploratory biomarker analysis through multi-omics of patient biopsies in prospective clinical trials, and development of new ADCs, e.g., bispecific ADCs and identification of novel antigens and/or payloads, to overcome ADC resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101353"},"PeriodicalIF":21.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925903","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":"IFNα2b modulates anti-tumor immune responses involving STAT3-associated dendritic cell dysfunction in JAK2v617f-positive myeloproliferative neoplasms","authors":"Lijun Fang ,&nbsp;Rongfeng Fu ,&nbsp;Huan Dong ,&nbsp;Wenhui Zhang ,&nbsp;Yuchen Gao ,&nbsp;Yanmei Xu ,&nbsp;Wenjing Gu ,&nbsp;Zixuan Liu ,&nbsp;Huiyuan Li ,&nbsp;Wentian Wang ,&nbsp;Xiaolei Pei ,&nbsp;Ying Chi ,&nbsp;Yuan Zhou ,&nbsp;Jun Wei ,&nbsp;Ying Wang ,&nbsp;Lei Zhang","doi":"10.1016/j.drup.2026.101352","DOIUrl":"10.1016/j.drup.2026.101352","url":null,"abstract":"<div><h3>Aims</h3><div>To define <em>JAK2v617f</em>-induced immune alterations, focusing on STAT3-mediated dendritic cell dysfunction, and evaluate whether IFNα2b restores anti-tumor immunity in <em>JAK2v617f</em>-positive myeloproliferative neoplasms.</div></div><div><h3>Methods</h3><div>Integrated flow cytometry and single-cell RNA sequencing profiled immune landscapes and signaling pathways, while functional assays assessed dendritic cell differentiation, T cell activation, and IFNα2b-mediated immune restoration.</div></div><div><h3>Results</h3><div><em>JAK2v617f</em> was associated with increased STAT3 activation in myeloid cells, accompanied by elevated expression of immunosuppressive mediators such as FGL2, impaired monocyte-to-DC differentiation, reduced cDC1/cDC2 subsets, and diminished T cell activation, consistent with an immunosuppressive immune landscape. IFNα2b treatment was associated with attenuation of STAT3/FGL2 signaling and partial restoration of DC-mediated T cell priming, with more pronounced immunomodulatory effects observed in <em>JAK2v617f</em>-positive myeloproliferative neoplasms compared with other subtypes.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that <em>JAK2v617f</em> is associated with STAT3-dependent dendritic cell dysfunction that contributes to an immunosuppressive milieu. IFNα2b modulates this pathway and partially restores DC–T cell interactions, highlighting its potential as an immunomodulatory strategy in <em>JAK2v617f</em>-positive myeloproliferative neoplasms.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101352"},"PeriodicalIF":21.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902552","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":"2026-01-02","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":"Molecular profiling of chemotherapy-resistant breast cancer reveals DNA methylation remodeling associated with the acquisition of paclitaxel resistance","authors":"Lenka Trnkova ,&nbsp;Monika Burikova ,&nbsp;Andrea Soltysova ,&nbsp;Andrej Ficek ,&nbsp;Jana Plava ,&nbsp;Andrea Cumova ,&nbsp;Lucia Rojikova ,&nbsp;Kristina Jakic ,&nbsp;Eva Sedlackova ,&nbsp;Boris Tichy ,&nbsp;Vojtech Bystry ,&nbsp;Florence Busato ,&nbsp;Yimin Shen ,&nbsp;Miroslava Matuskova ,&nbsp;Lucia Kucerova ,&nbsp;Geir Frode Øy ,&nbsp;Gunhild Mari Mælandsmo ,&nbsp;Thomas Fleischer ,&nbsp;Jorg Tost ,&nbsp;Svetlana Miklikova ,&nbsp;Bozena Smolkova","doi":"10.1016/j.drup.2026.101350","DOIUrl":"10.1016/j.drup.2026.101350","url":null,"abstract":"<div><h3>Aims</h3><div>Chemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study aimed to investigate the role of DNA methylation in this complex process and evaluate the potential of the DNA methyltransferase inhibitor decitabine (DAC) in restoring chemosensitivity.</div></div><div><h3>Methods</h3><div>Paclitaxel (PAC)- and doxorubicin (DOX)- resistant BC cell lines were derived from luminal A (T-47D), triple-negative (MDA-MB-231), and HER2-positive (JIMT-1) models and characterized by molecular profiling and functional assays. The therapeutic effects of DAC and DOX were assessed in MDA-MB-231 xenografts, and integrative analyses of DNA methylation and gene expression identified pathways associated with resistance. Follow-up analyses were performed in PAC-resistant MAS98.12 patient-derived xenografts (PDX) and in clinical samples from the NeoAva trial (NCT00773695).</div></div><div><h3>Results</h3><div>Resistant cells exhibited a slow-cycling phenotype, reduced tumorigenicity, and widespread genomic alterations. PAC-resistant xenografts showed extensive methylation and transcriptomic reprogramming, partly restored by DAC, which increased Ki-67 expression and enhanced DOX responsiveness. In contrast, PDX tumors displayed less pronounced changes, predominantly hypomethylation, indicating distinct resistance mechanisms. Importantly, xenograft-derived CpG signatures stratified NeoAva patients by treatment response.</div></div><div><h3>Conclusions</h3><div>Chemoresistance in BC involves extensive genomic and epigenetic remodeling. Although DAC can modulate methylation and tumor phenotype, rational drug combinations will be required to overcome resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101350"},"PeriodicalIF":21.7,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895426","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":"AMPKα2 attenuates doxorubicin induced ferroptosis by promoting NCOA4 degradation in triple negative breast cancer","authors":"Xinjun Liu ,&nbsp;Zizhen Si ,&nbsp;Linbo Li ,&nbsp;Miao Zhou ,&nbsp;Ki-Young Lee ,&nbsp;Xidi Wang","doi":"10.1016/j.drup.2025.101349","DOIUrl":"10.1016/j.drup.2025.101349","url":null,"abstract":"<div><h3>Aims</h3><div>Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited therapeutic options and frequent chemoresistance. AMPK catalytic α-subunit 2 (AMPKα2) is implicated in development of chemoresistance in various cancers. However, the role of AMPKα2 in doxorubicin (DOX)-resistance in TNBC remains to be investigated.</div></div><div><h3>Methods</h3><div>The levels of AMPKα2 in DOX-resistant TNBC was examined by Western blotting. AMPKα2 functions on DOX induced ferroptosis were assessed by lipid peroxidation, intracellular iron, MDA, and GSH detection assays. Western blotting, qRT-PCR, co-IP, immunofluorescence staining and KFERQ-mCherry reporter assay were performed to demonstrate the role of AMPKα2 and its association with NCOA4 degradation.</div></div><div><h3>Results</h3><div>AMPKα2, rather than AMPKα1, was upregulated in DOX-resistant TNBC cells. AMPKα2 inhibited DOX-induced ferroptosis by suppressing NCOA4. AMPKα2 phosphorylated NCOA4 at S151, which enhanced the recognition of NCOA4 by HSC70, and the formation of NCOA4/HSC70/LAMP-2A complex to initiate CMA pathway mediated NCOA4 degradation. S151A mutation or AMPKα inhibitor abolished these biological effects and increased the vulnerability to DOX-induced ferroptosis.</div></div><div><h3>Conclusions</h3><div>AMPKα2 suppressed DOX-induced ferroptosis through phosphorylating NCOA4 at S151 to induce its CMA pathway dependent degradation. Targeting AMPKα2 could be a potential strategy to overcome DOX resistance in TNBC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101349"},"PeriodicalIF":21.7,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894006","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":"2025-12-29","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}