Drug Resistance Updates最新文献

{"title":"The role of synthetic lethality in overcoming cancer therapy resistance: Emerging paradigm and recent advances.","authors":"Qingyi Xiong, Jinmei Jin, Jiayi Lin, Bohan Zhang, Yixin Jiang, Zhe Sun, Lijun Zhang, Ye Wu, Guozhi Zhao, Jiang-Jiang Qin, Xin Luan","doi":"10.1016/j.drup.2025.101290","DOIUrl":"10.1016/j.drup.2025.101290","url":null,"abstract":"<p><p>Cancer therapy resistance remains a major barrier to successful treatment, often leading to reduced clinical efficacy or cancer relapse. Synthetic lethality (SL) has emerged as a promising strategy to exploit genetic vulnerabilities in cancer cells, allowing for more selective and less toxic therapies. By leveraging the genetic or non-genetic adaptations that cancer cells develop under therapeutic pressure, SL-based therapies provide a more precise and less toxic treatment approach. Additionally, SL-driven drug combinations not only delay development of drug resistance but also enhance therapeutic efficacy, representing a transformative shift in cancer management. A comprehensive understanding of SL mechanisms in the context of drug resistance is essential for advancing effective treatment strategies. This review highlights recent advances in SL research, emphasizing the gene screening techniques in overcoming cancer therapy resistance.</p>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"101290"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812629","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 covalent gambit: An irreversible inhibitor to checkmate drug resistance in tuberculosis","authors":"Chunxia Jiang, Dan Wang, Liujun Xu","doi":"10.1016/j.drup.2025.101314","DOIUrl":"https://doi.org/10.1016/j.drup.2025.101314","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"20 1","pages":"101314"},"PeriodicalIF":24.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261683","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":"Dissection of immunotherapeutic predictive versus prognostic transcriptional programs identifies SLC22A5-centric carnitine metabolism-driven resistance to anti-PD-(L)1 treatment in non-small cell lung cancer","authors":"Yu-Ze Wang ,&nbsp;Ning Gao ,&nbsp;Zhanwen Lin ,&nbsp;Si-Heng Wang ,&nbsp;Shichang Ai ,&nbsp;Zhanqi Wei ,&nbsp;Shuishen Zhang ,&nbsp;Junchao Cai ,&nbsp;Weixiong Yang ,&nbsp;Si-Cong Ma ,&nbsp;Chao Cheng","doi":"10.1016/j.drup.2025.101313","DOIUrl":"10.1016/j.drup.2025.101313","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Aims&lt;/h3&gt;&lt;div&gt;Prognostic and predictive biomarkers are two common biomarker types in clinics, with the former indicating the natural course of cancer regardless of treatment, and the latter determining the response to a specific regimen. Understanding the predictive versus prognostic effect of biomarkers is essential to understand treatment-specific response from the inherent prognosis of cancer. Herein, we aimed to uncover the predictive metabolic signatures specific to immunotherapy resistance by distinguishing the predictive versus prognostic effect of transcriptional programs in advanced non-small cell lung cancer (NSCLC) treated with immunotherapy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Clinical and transcriptomic data were collected from two randomized controlled trials, OAK (n = 699, discovery cohort) and POPLAR (n = 192, validation cohort) comparing immunotherapy with chemotherapy. Metabolic transcriptional signature scores were calculated through gene set variation analysis. Cox regression and interaction test were conducted to differentiate the predictive versus prognostic effect. Additionally, lung tumor-bearing murine models were established using &lt;em&gt;Slc22a5&lt;/em&gt;-overexpressing (OE) and control Lewis Lung Carcinoma (LLC) cells, and treated with immunotherapy or chemotherapy. The translational potential of an SLC22A5 (Solute Carrier Family 22 Member 5) inhibitor in combination with immunotherapy was assessed in preclinical setting. The tumor microenvironment was analyzed by flow cytometry, immunofluorescence, and Enzyme-Linked Immunosorbent Assay (ELISA) to validate the mechanistic findings.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Metabolic transcriptional programs were divided into four categories based on different predictive effects specific to immunotherapy or chemotherapy, among which carnitine metabolism stood out as the most prominent metabolic process contributing to the resistance to immunotherapy. Specifically, SLC22A5 as the only high-affinity carnitine transporter was remarkably upregulated in immunotherapy-resistant patients. The predictive effect of SLC22A5-centric carnitine metabolism for resistance to immunotherapy rather than chemotherapy was independently validated in an external randomized trial. Critically, preclinical models revealed that &lt;em&gt;Slc22a5&lt;/em&gt; overexpression drove resistance to immunotherapy but not chemotherapy, by fostering an immunosuppressive microenvironment characterized by M2 macrophage accumulation and CD8 + T cell exclusion. Furthermore, pharmacological inhibition of SLC22A5 by meldonium reshaped the tumor microenvironment toward a more inflamed state and re-sensitized resistant tumors to immunotherapy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our study elucidates the predictive versus prognostic effect of metabolic pathways in advanced NSCLC under immunotherapy. Tumor-intrinsic carnitine metabolism may predict and drive immunotherapy resistance, and targeting SLC22A5-mediated carnitine me","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101313"},"PeriodicalIF":21.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221841","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":"Microbiota in drug resistance","authors":"Ru Jia ,&nbsp;Chuan-xing Xiao ,&nbsp;Yong-hai Zhang ,&nbsp;Li-yang Hu ,&nbsp;Y. Jun-jun ,&nbsp;Rui Zuo ,&nbsp;Yu-fei Hu ,&nbsp;Yu-hao Xie ,&nbsp;Xue-lei Ma ,&nbsp;Qi Li ,&nbsp;Kai-jian Hou","doi":"10.1016/j.drup.2025.101311","DOIUrl":"10.1016/j.drup.2025.101311","url":null,"abstract":"<div><div>Drug resistance, particularly those of anticancer drugs and antibiotics, poses a significant challenge in the treatment of diseases, severely compromising therapeutic efficacy and patient survival rates. In recent years, an increasing number of studies have highlighted the dual role of microbiota in either promoting or mitigating drug resistance. The microbiome exists in symbiosis with the host, playing a crucial role in maintaining physiological functions and regulating immune responses. However, dysbiosis within the microbial community may induce or exacerbate drug resistance. While antibiotic-mediated depletion of gut microbiota has been proposed as a strategy to combat resistance, it may paradoxically lead to increased resistance or even worsen treatment outcomes. In this review, we focus on anticancer and antimicrobial agents as representative examples to elucidate the association of microbiome and drug resistance. We provide a detailed discussion on the mechanisms by which microbial dysbiosis contributes to development of drug resistance. Additionally, we systematically summarize the latest advancements in microbiota-targeted therapeutic strategies aimed at overcoming resistance, including fecal microbiota transplantation, probiotics and prebiotics, and bacterial engineering approaches. Finally, we discuss the potential clinical applications of microbiota-modulating strategies for overcoming drug resistance and examine the current challenges and future research directions in this field.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101311"},"PeriodicalIF":21.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158877","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":"Beyond the boundary: The emerging roles of ATP-binding cassette transporters in multidrug resistance (MDR) and therapeutic targeting in cancer","authors":"Dongmei Sun ,&nbsp;Letao Bo ,&nbsp;Chao Jiang ,&nbsp;Yanning Lan ,&nbsp;Bohan Zhang ,&nbsp;Chao Zhang ,&nbsp;Zhe-Sheng Chen ,&nbsp;Yuying Fan","doi":"10.1016/j.drup.2025.101310","DOIUrl":"10.1016/j.drup.2025.101310","url":null,"abstract":"<div><div>Multidrug resistance (MDR) remains a primary obstacle to successful cancer chemotherapy, with the overexpression of ATP-binding cassette (ABC) transporters being a principal cause. These transporters actively efflux a wide range of anticancer drugs, reducing their intracellular efficacy. Consequently, targeting ABC transporters represents a critical strategy for overcoming therapeutic resistance. This comprehensive review details the molecular architecture and functional mechanisms of all seven human ABC transporter subfamilies (ABCA-ABCG), elucidating their distinct roles in both cancer progression and the development of MDR. We trace the evolution of therapeutic interventions, from first, second, and third-generation small molecule inhibitors to the potential of natural products. Furthermore, this review explores advanced and emerging strategies designed to circumvent or neutralize ABC transporter activity. These include genetic approaches such as RNA interference and CRISPR-Cas9 gene editing, immunotherapy-based tactics like monoclonal antibodies and antibody-drug conjugates (ADCs), and the application of sophisticated nanoparticle delivery systems designed to bypass efflux mechanisms. By providing a holistic overview of the entire ABC transporter family and the broad array of strategies being developed to counteract their function, this article aims to equip researchers with a full-scope perspective on the field, identifying current challenges and illuminating future directions for combating MDR in cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101310"},"PeriodicalIF":21.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093862","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":"Gamma-synuclein drives bevacizumab resistance in colorectal cancer via VEGFR2 activation and angiogenesis","authors":"Caiyun Liu ,&nbsp;Lin Meng ,&nbsp;Lixin Wang ,&nbsp;Bin Dong ,&nbsp;Like Qu ,&nbsp;Chuanke Zhao ,&nbsp;Chengchao Shou","doi":"10.1016/j.drup.2025.101299","DOIUrl":"10.1016/j.drup.2025.101299","url":null,"abstract":"<div><h3>Background</h3><div>Resistance to Bevacizumab (Bev) remains a major obstacle in colorectal cancer (CRC) treatment. Gamma-synuclein (SNCG), overexpressed in tumor vasculature and cancer cells, is investigated here for its role in Bev resistance and therapeutic potential.</div></div><div><h3>Methods</h3><div>Using isogenic CRC models with SNCG overexpression or knockout, we assessed SNCG's impact on Bev response in vitro and in vivo. The therapeutic efficacy of combining Bev with an anti-SNCG monoclonal antibody (42#) was evaluated in Bev-resistant models. Mechanistic studies, including ELISA, Western blot, surface plasmon resonance (SPR), and molecular docking, explored interactions between SNCG, VEGF, and VEGFR2.</div></div><div><h3>Results</h3><div>SNCG overexpression reduced Bev sensitivity by impairing the inhibition of migration, invasion, and spheroid formation, whereas SNCG knockout enhanced therapeutic response. Molecular docking revealed that SNCG binds VEGFR2 at an allosteric site, forming a stable ternary complex (SNCG-VEGF-VEGFR2) with enhanced hydrogen bonding, which sustained VEGFR2 phosphorylation and angiogenesis. In vivo, SNCG-overexpressing tumors showed reduced responsiveness to Bev (42.8 % inhibition vs. 64.3 % in controls, <em>p</em> &lt; 0.05), while SNCG-deficient tumors exhibited a 3.2-fold increase in sensitivity. Combining Bev with 42# synergistically suppressed tumor growth (0.70 ± 0.36 g vs. 1.55 ± 0.41 g, <em>p</em> = 0.003), reduced metastatic burden (0.29 ± 0.23 g vs. 0.97 ± 0.42 g, <em>p</em> = 0.006), and extended median survival (86.8 vs. 69.8 days, <em>p</em> = 0.033) in Bev-resistant models.</div></div><div><h3>Conclusions</h3><div>SNCG drives Bev resistance in CRC by forming a ternary complex with VEGF and VEGFR2, enhancing VEGFR2 signaling and angiogenesis. Dual targeting of VEGF and SNCG represents a promising therapeutic strategy to overcome Bev resistance, with the potential to improve outcomes in CRC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101299"},"PeriodicalIF":21.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050623","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":"Overcoming multidrug resistance using small molecule dynamic inhibitors by hijacking nascent and inducing turnover of mature ABCG2 for degradation in lysosomes","authors":"Zizheng Dong ,&nbsp;Xiuzhen Fan ,&nbsp;JoAnne J Babula ,&nbsp;Shaobo Zhang ,&nbsp;Jing-Yuan Liu ,&nbsp;Jian-Ting Zhang","doi":"10.1016/j.drup.2025.101298","DOIUrl":"10.1016/j.drup.2025.101298","url":null,"abstract":"<div><div>ABCG2 has been associated with multidrug resistance (MDR) and protection of cancer stem cells. ABCG2 knockout had no apparent adverse effect on mice. Thus, ABCG2 is an interesting and perhaps an ideal target for drug discovery to overcome MDR and eliminate cancer stem cells. Although many ABCG2 inhibitors have been identified, few have moved into clinical testing and none has been approved. Thus, there is an unmet need for novel ABCG2 inhibitors. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTAC) and molecular-glues have been gaining traction with many in clinical trials, representing a new way targeting cytosolic proteins. However, TPD agents for membrane proteins are scarce. Recently, ABCG2 inhibitors with dynamic properties have been identified that they not only inhibit ABCG2 activity but also induce ABCG2 degradation. These dynamic inhibitors are unique and may represent a new class of TPD agents for membrane proteins and next generation inhibitors for development. Here, we investigated the mechanism of action of the dynamic inhibitor PZ-39 and its analogue PZ-39C8 and showed that they selectively bound to the extracellular loop between TM5-TM6 of ABCG2. This binding induces clathrin-dependent endocytosis of mature ABCG2 and hijacks nascent ABCG2, targeting them to lysosome via autophagy for degradation. PZ-39 also effectively induced ABCG2 loss and sensitized doxorubicin resistance in xenograft tumors. Thus, further investigation of dynamic ABCG2 inhibitors may lead to the next generation of therapeutics to overcome MDR in cancer chemotherapy and contribute to future design of TPD agents targeting membrane proteins.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101298"},"PeriodicalIF":21.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050622","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":"Polymeric micellar paclitaxel, cisplatin, and tislelizumab as first-line therapy for advanced unresectable esophageal squamous cell carcinoma: A phase II study with resistance profiling in poor responders","authors":"Caolu Liu ,&nbsp;Zipeng Wu ,&nbsp;Yingying Dai ,&nbsp;Shuyi Hu ,&nbsp;Lei Xia ,&nbsp;Xiaoyou Li ,&nbsp;Ruofan Yu ,&nbsp;Tianyi Liu ,&nbsp;Jingwen Li ,&nbsp;Fei Yan ,&nbsp;Lin Lu ,&nbsp;Yue Shi ,&nbsp;Yingying Jiang ,&nbsp;Jinghua Zhu ,&nbsp;Bo Shen ,&nbsp;Guoren Zhou ,&nbsp;Delin Liu ,&nbsp;Guochun Cao ,&nbsp;Xiaohua Wang ,&nbsp;Cheng Chen","doi":"10.1016/j.drup.2025.101300","DOIUrl":"10.1016/j.drup.2025.101300","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the efficacy and safety of polymeric micellar paclitaxel (Pm-Pac), cisplatin, and tislelizumab as first-line therapy for advanced/metastatic esophageal squamous cell carcinoma (ESCC), addressing limitations of conventional paclitaxel regimens related to steroid-induced immunosuppression.</div></div><div><h3>Methods</h3><div>This phase II clinical trial enrolled 27 treatment-naïve patients with stage IV ESCC. The regimen consisted of Pm-Pac (230 mg/m²), cisplatin (70 mg/m²), and tislelizumab (200 mg) administered on day 1 of 21-day cycles. After two induction cycles, non-progressive patients received two additional cycles, followed by 12-month tislelizumab maintenance. Primary endpoint: objective response rate (ORR); secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Exploratory analyses included blood counts, tumor markers, lymphocyte subsets, survival analysis, Kruskal-Wallis tests, clustering, and LASSO regression.</div></div><div><h3>Results</h3><div>The regimen achieved an ORR of 62.96 % (95 % CI: 0.45–0.81) with complete response (CR) in 7.4 % and partial response (PR) in 55.6 % of patients. Median PFS was 10.2 months, with 1-year OS probability of 81.48 %. Treatment was well-tolerated without grade ≥ 3 treatment-related adverse events or deaths. Exploratory predictive analyses suggested potential correlations between outcomes and hyperkalemia, CD4 +CD25 + T cells, lung metastases, and distant lymph node metastases.</div></div><div><h3>Conclusions</h3><div>The Pm-Pac-based chemoimmunotherapy suggests encouraging efficacy and favorable safety in advanced ESCC, supporting its potential as a first-line steroid-free option. These findings highlight the role of nanotechnology in optimizing chemoimmunotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101300"},"PeriodicalIF":21.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082402","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":"Erratum to “A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+ CD24- enriched breast cancer stem-like cells” [Drug Resist. Updates 66 (2023) 100903]","authors":"Caigang Liu ,&nbsp;Yixiao Zhang ,&nbsp;Jiujiao Gao ,&nbsp;Qi Zhang ,&nbsp;Lisha Sun ,&nbsp;Qingtian Ma ,&nbsp;Xinbo Qiao ,&nbsp;Xinnan Li ,&nbsp;Jinchi Liu ,&nbsp;Jiawen Bu ,&nbsp;Zhan Zhang ,&nbsp;Ling Han ,&nbsp;Dongyu Zhao ,&nbsp;Yongliang Yang","doi":"10.1016/j.drup.2025.101297","DOIUrl":"10.1016/j.drup.2025.101297","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101297"},"PeriodicalIF":21.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006825","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":"Staphylococcus aureus manipulates osteocytes to cause persistent chronic osteomyelitis and antibiotic resistance via pyroptosis pathway suppression","authors":"Yuanqing Cai ,&nbsp;Hongxin Hu ,&nbsp;Yang Chen ,&nbsp;Jiayu Li ,&nbsp;Chaofan Zhang ,&nbsp;Xuhui Yuan ,&nbsp;Wenbo Li ,&nbsp;Changyu Huang ,&nbsp;Yiming Lin ,&nbsp;Zeyu Zhang ,&nbsp;Bin Yang ,&nbsp;Zida Huang ,&nbsp;Wenming Zhang ,&nbsp;Xinyu Fang","doi":"10.1016/j.drup.2025.101295","DOIUrl":"10.1016/j.drup.2025.101295","url":null,"abstract":"<div><h3>Aims</h3><div>In chronic osteomyelitis, the cortical bone serves as the primary site for long-term persistence of <em>Staphylococcus aureus</em> (<em>S. aureus</em>), the present study aimed to explore the mechanisms of immune evasion and antibiotic resistance remain incompletely understood.</div></div><div><h3>Methods</h3><div>Clinical methicillin-resistant <em>S. aureus</em> (MRSA) isolates, were collected and analyzed. Panton-Valentine leukocidin (PVL) expression levels were quantified via real-time PCR. The impact of PVL on pyroptosis was evaluated by infecting osteocytes and measuring caspase-1 activation and IL-1β release. Osteoclastogenesis and pathological bone formation were examined through TRAP staining and micro-CT. To assess therapeutic potential, pyroptosis was pharmacologically induced using disodium 4,4’-dimethoxy-5,6,5’,6’-dimethylene dioxybiphenyl-2,2’-disulfonate (DMB), followed by evaluation of antibiotic efficacy and bone remodeling in osteomyelitis model.</div></div><div><h3>Results</h3><div>We observed in clinical cases that the survival rate of MRSA small colony variants (SCVs) in cortical bone is higher than that of non-SCV strains, with SCVs demonstrating characteristic antibiotic resistance through reduced metabolic activity. The PCR results demonstrated that compared to wild-type, MRSA SCVs exhibited significantly reduced expression levels of PVL, this low-PVL-expression phenotype markedly suppresses the activation of the pyroptosis pathway following infection. Furthermore, we discovered that during the adaptation to the intra-cortical environment, the global regulatory factor Sae and the protease aureolysin mediate the active downregulation of PVL, which resulted in targeted inhibition of osteocyte pyroptosis. The suppression of osteocyte pyroptosis simultaneously diminishes the host immune response, MRSA colonization, and antibiotics resistance. Pharmacological induction of pyroptosis via DMB significantly enhanced antibiotic efficacy, as well as alleviated pathological bone formation in chronic osteomyelitis.</div></div><div><h3>Conclusions</h3><div>MRSA modulates its own virulence factors to create a favorable space and environment for long-term survival within the cortical bone, and therapeutic strategies targeting osteocyte pyroptosis may represent a potential strategy of eradicating MRSA from cortical bone.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101295"},"PeriodicalIF":21.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021104","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}