Drug Resistance Updates最新文献

{"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":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial cells sense temozolomide resistance to facilitate monocyte-derived macrophage infiltration in glioblastoma","authors":"Wei Gao ,&nbsp;Jianliang Huang ,&nbsp;Kun Deng ,&nbsp;Xiang Lin ,&nbsp;Xinmiao Long ,&nbsp;Xuetong Li ,&nbsp;Meng Huang ,&nbsp;Xiangyu Wang ,&nbsp;Xiaoling She ,&nbsp;Qing Liu ,&nbsp;Minghua Wu","doi":"10.1016/j.drup.2025.101329","DOIUrl":"10.1016/j.drup.2025.101329","url":null,"abstract":"<div><h3>Aims</h3><div>Glioblastoma (GBM), particularly mesenchymal and recurrent GBM, often develops resistance to temozolomide (TMZ) and is characterized by extensive infiltration of monocyte-derived macrophages (MDM), which contributes to treatment failure. However, the mechanisms through which TMZ-resistant GBM recruits MDM remain poorly understood. This study aims to investigate the molecular drivers of MDM infiltration in the context of TMZ resistance and to identify potential therapeutic targets to disrupt this process.</div></div><div><h3>Methods</h3><div>Patient-derived GBM organoid (GBO) was utilized as a model system. We performed molecular profiling to identify genes upregulated in TMZ-resistant recurrent GBO. Endothelial cells (ECs) cultures and preclinical GBM models were used to examine disruption of tight junctions and monocyte infiltration. Mechanistic studies employed genetic knockdown, pharmacological inhibition, and assays, including Chromatin immunoprecipitation-quantitative PCR, Western blot, and immunostaining, to validate pathway activity and protein interactions.</div></div><div><h3>Results</h3><div>COL6A1 (Collagen type VI alpha 1 chain) was significantly upregulated in TMZ-resistant recurrent GBO and associated with poor survival. COL6A1 is bound to ITGB1 (Integrin beta-1) on ECs, leading to disruption of tight junctions via UBD (Ubiquitin-like modifier D)-mediated degradation of claudin-5. Furthermore, COL6A1 activated the FAK/SRC/Hippo/YAP signaling axis, which promoted lactylation of the transcription factor IKZF1 (IKAROS family zinc finger 1) at lysine 255. Lactylated IKZF1 translocated to the nucleus and recruited the chromatin remodeler Chromodomain-helicase-DNA-binding protein 1 to enhance UBD transcription, thereby promoting endothelial barrier breakdown and monocyte infiltration. Treatment with lenalidomide (LEN), an IKZF1 inhibitor, restored claudin-5 expression, reduced MDM accumulation, and re-sensitized TMZ-resistant tumors to chemotherapy in preclinical models.</div></div><div><h3>Conclusion</h3><div>This study identifies a novel signaling cascade whereby TMZ-resistant GBM secretes COL6A1 to activate an IKZF1-UBD axis in ECs, disrupting blood vessel integrity and facilitating MDM infiltration. Our findings delineate the pivotal mechanism by which tumor cells engage ECs to drive MDM infiltration - a linchpin part of the positive-feedback loop that couples TMZ resistance to MDM influx. Targeting IKZF1 with LEN represents a promising strategy for restoring endothelial barrier function, reducing MDM infiltration, and enhancing chemosensitivity in GBM.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101329"},"PeriodicalIF":21.7,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of blaOXA-48 into a Col156 plasmid drove a carbapenem-resistant Escherichia coli ST131 outbreak in New Zealand: Global genomic evidence for the gene’s multilayered dissemination","authors":"Rhys T. White ,&nbsp;Craig N. Thornley ,&nbsp;Max Bloomfield ,&nbsp;Kristin Dyet ,&nbsp;Juliet Elvy ,&nbsp;Hermes Perez ,&nbsp;Allan Hardaker ,&nbsp;Michael Harrington ,&nbsp;Simon Jackson ,&nbsp;Matthew Kelly ,&nbsp;Loushy Mangalasseril ,&nbsp;Annette Nesdale ,&nbsp;Xiaoyun Ren ,&nbsp;Jenny Szeto ,&nbsp;Claire Underwood ,&nbsp;David Winter ,&nbsp;Rosemary Woodhouse ,&nbsp;Zuyu Yang","doi":"10.1016/j.drup.2025.101327","DOIUrl":"10.1016/j.drup.2025.101327","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the genetic diversity in OXA-48-producing <em>Escherichia coli</em> ST131 in a New Zealand community outbreak, and to characterize the mobile genetic elements carrying <em>bla</em>_OXA-48, with emphasis on the gene’s global dissemination.</div></div><div><h3>Methods</h3><div>Forty outbreak isolates underwent short-read sequencing; 36 also underwent long-read sequencing. Bayesian phylogenetics reconstructed the emergence and spread of the outbreak. A pangenome graph of 543 Col156 plasmids and 806 global <em>bla</em>_OXA-48-positive contigs were analyzed to assess structural diversity, mobility, and global distribution.</div></div><div><h3>Results</h3><div>The outbreak clone likely emerged circa 2017, following a single introduction into New Zealand after acquiring <em>bla</em>_OXA-48 on a 7872 bp Col156 plasmid. It shares ancestry (circa 2009) with Southeast Asian <em>E. coli</em> ST131 genomes. Long-read sequencing and pangenome graph analyses identified a single IS<em>1</em>-mediated transposition of <em>bla</em>_OXA-48 into a Col156 plasmid backbone, observed across species and continents. Globally, <em>bla</em>_OXA-48 is present in diverse plasmid contexts and insertion sequence arrangements and is widely distributed among Enterobacterales.</div></div><div><h3>Conclusions</h3><div>This is the first high-resolution genomic reconstruction of a community-associated <em>bla</em>_OXA-48 outbreak, identifying a compact Col156 plasmid as a key vector driving carbapenem resistance. Our findings demonstrate the value of complete genome assemblies and pangenome graph analyses in resolving the structural and evolutionary dynamics of antimicrobial resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101327"},"PeriodicalIF":21.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis and the cGAS–STING pathway into precision nano-immuno-theranostics: A mechanistic paradigm for reversing drug resistance in hepatocellular carcinoma","authors":"Alaa Elmetwalli","doi":"10.1016/j.drup.2025.101326","DOIUrl":"10.1016/j.drup.2025.101326","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) represents a formidable therapeutic challenge, with intrinsic and acquired resistance mechanisms severely limiting treatment efficacy and contributing to dismal patient outcomes. This comprehensive review examines the emerging paradigm of precision nano-immuno-theranostics, specifically focusing on ferroptosis-STING coupled platforms as innovative strategies for overcoming multifaceted HCC resistance. This study systematically analyzes five key nanotechnology approaches: lipid nanoparticles (LNPs) for dual-cargo delivery, GPC3-targeted immunotherapeutic platforms, multimodal theranostic systems, sonodynamic therapy constructs, and spatial transcriptomics-guided precision designs. The strategic integration of ferroptosis induction—an iron-dependent cell death mechanism uniquely suited to the iron-rich hepatic microenvironment—with cGAS-STING pathway activation establishes a bidirectional synergistic loop wherein ferroptotic tumor death generates endogenous STING activation, which reciprocally sensitizes cancer cells to ferroptosis. This dual-targeting approach converts immunologically \"cold\" HCC tumors into inflamed \"hot\" therapeutic targets, achieving 78–91 % tumor growth inhibition and 4.2–4.8-fold increases in CD8 + tumor-infiltrating lymphocytes in preclinical models, substantially exceeding conventional monotherapies (sorafenib: 45–52 %; checkpoint inhibitors: 35–48 %). Mechanistically, ferroptosis-STING coupling simultaneously addresses three critical resistance modalities: chemoresistance through GPX4/NRF2 axis collapse, immunoresistance via tumor microenvironment reprogramming, and metabolic resistance by disrupting HIF-1α/STAT3-mediated adaptation. Despite compelling preclinical evidence, translation to clinical practice faces substantial challenges in manufacturing scalability, regulatory approval pathways for combination nanotechnology products, biomarker-driven patient stratification, and long-term safety assessment. This review critically evaluates current nano-immuno-theranostic platforms, provides quantitative comparative analysis against existing HCC therapies, identifies critical translational gaps, and proposes strategic solutions spanning adaptive regulatory frameworks, continuous manufacturing innovations, and precision medicine integration. The convergence of nanotechnology, immunotherapy, and multi-omic profiling offers unprecedented opportunities for developing next-generation HCC therapeutics capable of dismantling the complex resistance networks that characterize this aggressive malignancy, with first-in-human trials anticipated in 2025–2027 and potential regulatory approval trajectories extending to 2030.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101326"},"PeriodicalIF":21.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509260","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":"Three decades of ESKAPEE antimicrobial resistance: Emerging burdens in working-age individuals and high-income regions","authors":"Xiuling Song,&nbsp;Liang Wang,&nbsp;Bing Gu","doi":"10.1016/j.drup.2025.101325","DOIUrl":"10.1016/j.drup.2025.101325","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101325"},"PeriodicalIF":21.7,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498786","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":"Loss of cyclin C drives resistance to anti-TIGIT therapy by upregulating CD155-mediated immune evasion","authors":"Shiyu Mao ,&nbsp;Yadong Guo ,&nbsp;Chengyuan Dong ,&nbsp;Dongdong Wang ,&nbsp;Xinbo Wang ,&nbsp;Linjun Weng ,&nbsp;Yanrong Yang ,&nbsp;Yaxu Li ,&nbsp;Tingting Niu ,&nbsp;Qi Wu ,&nbsp;Zening Zheng ,&nbsp;Zezhi Shan ,&nbsp;Xiao Tan ,&nbsp;Yaohui Gao ,&nbsp;Jiali Jin ,&nbsp;Ping Wang ,&nbsp;Xin Ge ,&nbsp;Bing Shen ,&nbsp;Xudong Yao ,&nbsp;Lan Fang","doi":"10.1016/j.drup.2025.101318","DOIUrl":"10.1016/j.drup.2025.101318","url":null,"abstract":"<div><h3>Aims</h3><div>CD155 is an immune checkpoint protein expressed in tumor cells that interacts with its ligand T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on natural killer (NK) cells and T cells, mediating inhibitory regulation on immune cells. Blockade of the CD155-TIGIT interaction has demonstrated clinical benefits in patients with advanced cancers. The transcriptional and post-translational mechanisms governing CD155 expression remain largely unknown.</div></div><div><h3>Methods</h3><div>To identify regulators of CD155, we conducted a genome-wide CRISPR-Cas9 screen in cancer cells. Surface CD155 protein levels were analyzed via flow cytometry. The role of candidate regulators was validated through loss- and gain-of-function experiments with flow cytometry, Western blot, quantitative PCR, and chromatin immunoprecipitation (ChIP) assays. Additionally, ubiquitination assay was performed to examine post-translational modifications. Functional studies, including NK and T cell cytotoxicity assays, were conducted to assess the immune modulatory effects of CD155 regulation. Clinical relevance was evaluated by analyzing Cyclin C (CCNC) and CD155 expression in datasets of cancer patients who underwent immune checkpoint blockade therapy.</div></div><div><h3>Results</h3><div>The CRISPR-Cas9 screen identified CCNC as a transcriptional suppressor of CD155. <em>CCNC</em> knockout led to increased surface CD155 expression in cancer cell lines. Mechanistically, CCNC inhibited CD155 transcription by suppressing the activity of the transcription factor FOSL2. Furthermore, CCNC was found to be ubiquitinated and degraded by the E3 ubiquitin ligase FBXO11, suggesting a post-translational regulatory mechanism. Functionally, loss of CCNC promoted CD155 upregulation, thereby enhancing tumor immune evasion from NK and T cell-mediated responses. Clinically, CCNC expression was negatively correlated with CD155 levels in cancer patients, particularly those receiving immune checkpoint blockade therapy.</div></div><div><h3>Conclusion</h3><div>This study identifies a previously unrecognized master regulator CCNC that functions as a suppressor of CD155-mediated cancer immune evasion. The findings of this study suggest that tumors with low CCNC expression may be resistant to monotherapy and highlight a combination immunotherapy (TIGIT/PD-1 co-blockade) as a promising anti-cancer therapeutic strategy to overcome immune evasion in CCNC-deficient tumors.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101318"},"PeriodicalIF":21.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485479","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":"Y10 phosphorylation of LDHA promotes the release of extracellular vesicle-derived circSEPT9 to enhance the chemoresistance of triple negative breast cancer cells via modulation of miR-515–5p/KIAA1429 axis","authors":"Yueping Wang ,&nbsp;Ziyun Zhang ,&nbsp;Juan Gu ,&nbsp;Ming Zhou ,&nbsp;Jiankang Huang ,&nbsp;Daoping Zhou ,&nbsp;Xuedong Wang","doi":"10.1016/j.drup.2025.101324","DOIUrl":"10.1016/j.drup.2025.101324","url":null,"abstract":"<div><h3>Objective</h3><div>Extracellular vesicle (EV)-derived RNAs play crucial roles in cancer biology and therapeutic resistance. This study investigated how EV-derived circSEPT9 mediates doxorubicin (DOX) resistance in triple negative breast cancer (TNBC).</div></div><div><h3>Methods</h3><div>TNBC tissues and samples were analyzed alongside MDA-MB-231 and MDA-MB-231/ADR cells. The molecular interplay among circSEPT9, KIAA1429, and miR-515–5p was explored to elucidate the regulatory axis underlying drug resistance. EVs were purified to assess the clinical diagnostic potential of EV-circSEPT9. Functional assays employing lactate dehydrogenase A (LDHA) knockdown and rescue with Flag-tagged human LDHA WT or Y10F mutant constructs were conducted to examine the significance of LDHA Y10 phosphorylation in EV-circSEPT9 release and DOX resistance.</div></div><div><h3>Results</h3><div>circSEPT9 silencing impaired proliferation, invasion, and colony formation of DOX-resistant TNBC cells while increasing their sensitivity to DOX through suppression of KIAA1429-mediated m6A modification. EVs from resistant cells transferred circSEPT9 to sensitive cells, thereby enhancing their drug resistance and tumor growth capacity. LDHA Y10 phosphorylation was found to be indispensable for EV-circSEPT9 secretion and the subsequent intercellular transfer of DOX resistance.</div></div><div><h3>Conclusion</h3><div>Phosphorylated LDHA (Y10) promotes EV-circSEPT9 secretion, elevating intracellular circSEPT9 levels in recipient TNBC cells. By functioning as a competing endogenous RNA (ceRNA) that sponges miR-515–5p, circSEPT9 upregulates KIAA1429, augments m6A methylation, and drives the development of chemoresistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101324"},"PeriodicalIF":21.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462288","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":"Metabolite-driven reprogramming of bacterial persisters: Mechanisms and therapeutic opportunities for overcoming antibiotic tolerance","authors":"Yixiao Song ,&nbsp;Zifan Ye ,&nbsp;Yipeng Wang","doi":"10.1016/j.drup.2025.101322","DOIUrl":"10.1016/j.drup.2025.101322","url":null,"abstract":"<div><div>Bacterial persisters constitute a heterogeneous subpopulation of dormant or slow-growing cells capable of surviving harsh environmental conditions, including antibiotic exposure. These cells are strongly associated with the failure of clinical antibiotic therapies and the recurrence of chronic bacterial infections. A comprehensive understanding of the physiological features of bacterial persisters is therefore critical for the development of targeted interventions aimed at overcoming the limitations of conventional antibiotic treatments. In this review, we summarize current models of bacterial persister formation, with particular emphasis on the pivotal role of reduced metabolic activity in mediating antibiotic tolerance. We further elucidate the mechanisms through which exogenous metabolites—such as sugars, lipids, and nucleic acid derivatives—induce metabolic reprogramming, thereby reversing multidrug resistance in bacterial persisters. Furthermore, we summarized the major barriers limiting the clinical translation of metabolite-assisted “wake-and-kill” strategies and outlined future prospects for their application. In conclusion, restoring bacterial metabolic activity through targeted metabolite interventions represents a promising avenue to overcome antibiotic tolerance, paving the way for next-generation therapeutic strategies against persistent infections.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101322"},"PeriodicalIF":21.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441918","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":"Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance","authors":"Cheng Li ,&nbsp;Wei Xiong ,&nbsp;Jiahao Liu ,&nbsp;Ke Li ,&nbsp;Haoxiang Wang ,&nbsp;Zhengxiang Wang ,&nbsp;Feiyu Liu ,&nbsp;Jianliang Shen ,&nbsp;Zaigang Zhou ,&nbsp;Shenpeng Ying ,&nbsp;Long Wang","doi":"10.1016/j.drup.2025.101323","DOIUrl":"10.1016/j.drup.2025.101323","url":null,"abstract":"<div><div>CD276, is a fatal recently discovered immune checkpoint proteins of B7 family. Due to the not clearly uncovered signal pathways that involved in the expression of CD276 in tumors, few strategies were discovered to regulate CD276. Here, we newly discovered that abnormal tumor mitochondrial activation played a vital important role in raising CD276 expression through targeting AMPK/mTOR signal pathway. Then, it was also revealed that clinical usable lipid-lowering drugs with mitochondria oxidative phosphorylation (OXPHOS) and glycolysis inhibiting capacity, like fenofibric acid (FFA), exhibited desired programmed death ligand-1 (PD-L1) and CD276 co-suppression capacity. To better deliver FFA to tumor mitochondria, IR-FFA was synthesized by linking the mitochondria-targeting heptamethylene cyanine IR-68 with FFA, followed by self-assembly with albumin (Alb) to create IR-FFA@Alb nanoparticles. By doing so, the dosage needed for IR-FFA@Alb to depress CD276 and PD-L1 expression was 100 times lower than free FFA. Then, IR-FFA@Alb monotherapy effectively inhibited tumor growth both <em>in vitro</em> and <em>in vivo</em>. Moreover, the combination therapy of IR-FFA@Alb nanoparticles and radiotherapy (RT) effectively avoid the frequently occurred immune tolerance phenomenon of RT by co-depression CD276 and PD-L1. These results altogether showed the possibility of using lipid-lowering drugs as multi-functional immune checkpoint inhibitors to sensitize tumor therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101323"},"PeriodicalIF":21.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441447","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":"Disruption of NANOG-driven epithelial-mesenchymal transition (EMT) and self-renewal restores drug sensitivity in colorectal cancer","authors":"Kiarash Saleki ,&nbsp;Sameerah Shaheen ,&nbsp;Miao Xue ,&nbsp;Amirreza Mazloomi ,&nbsp;Sepideh Youssefi ,&nbsp;Hossein Kashfi ,&nbsp;Mehreen Ahmed ,&nbsp;Roya Babaei-Jadidi ,&nbsp;Bradley Spencer-Dene ,&nbsp;Dominique Bonnet ,&nbsp;Chris Denning ,&nbsp;Abdolrahman S. Nateri","doi":"10.1016/j.drup.2025.101321","DOIUrl":"10.1016/j.drup.2025.101321","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the regulatory role of NANOG in genes associated with stemness, symmetric division, and therapeutic resistance in colorectal cancer stem-like cells (CRC-SCs), with a focus on ERK/GSK-3β/β-catenin signalling and epithelial-mesenchymal transition (EMT), in order to evaluate the translational potential of targeting NANOG-associated signalling pathways.</div></div><div><h3>Methods</h3><div>Stemness, signalling activity, and cell division modes were analysed using 3D colonospheres enriched for CRC-SCs. Drug responses to the MEK inhibitor U0126 and the GSK-3β inhibitor TDZD-8 were assessed in CRC patient-derived organoids (PDOs), alongside molecular assays, immunohistochemistry with H-score quantification in xenograft models, and molecular dynamics simulations.</div></div><div><h3>Results</h3><div>NANOG overexpression enhanced the expression of stemness-associated genes, promoted symmetric cell division, and activated ERK/GSK-3β signalling, contributing to increased sphere formation. Inhibition of MEK and GSK-3β reduced EMT, cell proliferation, and symmetric division in CRC-SCs. NANOG-mediated dysregulation of ERK/GSK-3β altered β-catenin signalling and disrupted E-cadherin-dependent cell-cell adhesion. Molecular simulations and drug assays demonstrated that TDZD-8 and U0126 interfere with NANOG-DNA binding and β-catenin/E-cadherin interactions.</div></div><div><h3>Conclusions</h3><div>NANOG drives CRC-SC maintenance via ERK/GSK-3β/β-catenin signalling and EMT modulation. This study offers significant insights into the translational impact of targeting NANOG and its downstream pathways with small-molecule inhibitors U0126 and TDZD-8 and presents a promising strategy to reduce CRC-SCs stemness, functionality, and tumourigenicity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101321"},"PeriodicalIF":21.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441940","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}