Drug Resistance Updates最新文献

{"title":"Corrigendum to “Opposite evolution of pathogenicity driven by in vivo wzc and wcaJ mutations in ST11-KL64 carbapenem-resistant Klebsiella pneumoniae” [Drug Resist. Updat. 66 (2023) 100891]","authors":"Jintao He , Qiucheng Shi , Zhifu Chen , Wang Zhang , Peng Lan , Qingye Xu , Huangdu Hu , Qiong Chen , Jianzhong Fan , Yan Jiang , Belinda Loh , Sebastian Leptihn , Quanming Zou , Jinyong Zhang , Yunsong Yu , Xiaoting Hua","doi":"10.1016/j.drup.2025.101244","DOIUrl":"10.1016/j.drup.2025.101244","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101244"},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891423","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":"Long non-coding RNA LRTOR drives osimertinib resistance in non-small cell lung cancer by boosting YAP positive feedback loop","authors":"Zhimin Miao, Zhou Sha, Jianzhong He, Yongkai Liang, Lihua Tan, Yuxin Zhao, Xiaobing Cui, Jinmiao Zhong, Ruting Zhong, Huijun Liang, Wendi Yue, Boyang Qiu, Yunzhen Gao, Lan Zhang, Zixin Teng, Zeen He, Li Chen, Rufei Xiao, Xiaofeng Pei, Chengwei He","doi":"10.1016/j.drup.2025.101245","DOIUrl":"https://doi.org/10.1016/j.drup.2025.101245","url":null,"abstract":"The therapeutic efficacy of osimertinib (OSI) in EGFR-mutant lung cancer is ultimately limited by the onset of acquired resistance, of which the mechanisms remain poorly understood. Here, we identify a novel long non-coding RNA, LRTOR, as a key driver of OSI resistance in non-small cell lung cancer (NSCLC). Clinical data indicate that elevated LRTOR expression correlates with poor prognosis in OSI-resistant patients. Functionally, LRTOR promotes tumor growth and confers OSI resistance both <ce:italic>in vitro</ce:italic> and <ce:italic>in vivo</ce:italic>. Mechanistically, LRTOR shields YAP from LATS-mediated phosphorylation at Ser127 and Ser381, preventing its proteasomal degradation. Furthermore, LRTOR facilitates the interaction between YAP and KCMF1, promoting K63-linked ubiquitination, nuclear translocation of YAP, and formation of the YAP/TEAD1 transcriptional complex, which in turn triggers the transcription of LRTOR, establishing a positive feedback loop that amplifies oncogenic signaling of YAP and consequently induces OSI resistance. LRTOR depletion by siRNA restores OSI sensitivity in resistant tumors, as demonstrated in patient-derived organoid xenograft models. Our findings unveil LRTOR as a central regulator of OSI resistance in NSCLC and propose it as a promising therapeutic and prognostic target for overcoming acquired OSI resistance in EGFR-mutant lung cancer.","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"1 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901717","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":"Lactylation in cancer progression and drug resistance","authors":"Yuxiu Sun ,&nbsp;He Wang ,&nbsp;Zhe Cui ,&nbsp;Tingting Yu ,&nbsp;Yuanming Song ,&nbsp;Haolai Gao ,&nbsp;Ruihong Tang ,&nbsp;Xinlei Wang ,&nbsp;Binru Li ,&nbsp;Wenxin Li ,&nbsp;Zhe Wang","doi":"10.1016/j.drup.2025.101248","DOIUrl":"10.1016/j.drup.2025.101248","url":null,"abstract":"<div><div>Lactate plays a crucial role as an energy substrate, metabolite, and signaling molecule in cancer. Lactate has long been considered a byproduct of glycolysis. Still, the lactate shuttle hypothesis has changed the lactate paradigm, revealing the implications of lactate in cellular metabolism and cellular communications that can transcend the compartment barrier and occur within and between different cells, tissues, and organs. Due to the Warburg effect, the tumor produces a large amount of lactate, thus creating a low-nutrition, hypoxic, and low-pH tumor microenvironment (TME). Consequently, immunosuppressive networks are built to acquire immune evasion potential and regulate tumor growth. Lactylation is a newly discovered post-translational modification of lysine residues with the capacity for transcriptional regulation via histone modification and modulation of non-histone protein functions, which links gene regulation to cellular metabolism by aberrant metabolism activity and epigenetic modification. There is growing evidence that lactylation plays a crucial role in cancer progression and drug resistance. Targeting lactylation enzymes or metabolic pathways has shown promising effects in suppressing cancer progression and drug resistance, highlighting the therapeutic potential of this modification. Therefore, in this review, we offer a systematic overview of lactate homeostasis in physiological and pathological processes as well as discuss the influence of lactylation in cancer progression and drug resistance and underlying molecular mechanisms, providing a theoretical basis for further research.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101248"},"PeriodicalIF":15.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874194","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":"MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance","authors":"Jiawen Xu ,&nbsp;Bo Wang ,&nbsp;Qiaoyu Liu ,&nbsp;Sheng Guo ,&nbsp;Chen Chen ,&nbsp;Jun Wu ,&nbsp;Xiaoya Zhao ,&nbsp;Mengmeng Li ,&nbsp;Zhuang Ma ,&nbsp;Shimeng Zhou ,&nbsp;Yun Qian ,&nbsp;Yijin Huang ,&nbsp;Zhangding Wang ,&nbsp;Chuanjun Shu ,&nbsp;Qingxiang Xu ,&nbsp;Jingjing Ben ,&nbsp;Qiang Wang ,&nbsp;Shouyu Wang","doi":"10.1016/j.drup.2025.101246","DOIUrl":"10.1016/j.drup.2025.101246","url":null,"abstract":"<div><div>RNA-binding proteins (RBPs) are critical regulators in tumorigenesis and therapy resistance by modulating RNA metabolism. However, the role of RBPs in hepatocarcinogenesis and progression remains elusive. Here, RBPs screening and integrating analyses identify major vault protein (MVP) as an oncogenic RBP in the occurrence of hepatocellular carcinoma (HCC) and sorafenib resistance via suppressing ferroptosis. Mechanistically, reactive oxygen species (ROS) induces STAT3-mediated MVP transcription activation and high expression in HCC cells. Subsequently, phosphoglycerate mutase family member 5 (PGAM5) directly dephosphorylates MVP at S873, facilitating its binding to the mRNA of iron-sequestering cytokine LCN2 and maintains its stability, thereby attenuating ferroptosis by reducing lipid peroxidation and intracellular Fe²⁺ content following sorafenib treatment. Notably, tenapanor, a potent pharmacological inhibitor of MVP, effectively disrupts the interaction between MVP and LCN2 mRNA and enhances ferroptosis and sorafenib sensitivity. Collectively, these findings underscore the central role of MVP in hepatocarcinogenesis and offer promising avenues to improve HCC treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101246"},"PeriodicalIF":15.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855147","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":"KpnK48 clone driving hypervirulent carbapenem-resistant Escherichia coli epidemics: Insights into its evolutionary trajectory similar to Klebsiella pneumoniae","authors":"Meng Wang ,&nbsp;Longyang Jin ,&nbsp;Ruobing Wang ,&nbsp;Qi Wang ,&nbsp;Shuyi Wang ,&nbsp;Xingyu Wu ,&nbsp;Chaoqun Yao ,&nbsp;Jukka Corander ,&nbsp;Hui Wang","doi":"10.1016/j.drup.2025.101243","DOIUrl":"10.1016/j.drup.2025.101243","url":null,"abstract":"<div><h3>Aims</h3><div>Hypervirulent and carbapenem-resistant pathogens posed a significant and growing threat to global public health. This study focused on the rapid spread of a hypervirulent carbapenem-resistant <em>E. coli</em> (hv-CREC) subclone and its genomic resembles with hypervirulent carbapenem-resistant <em>K. pneumoniae</em> (hv-CRKP), driven by recombination impacting both chromosomal and plasmid gene content.</div></div><div><h3>Methods</h3><div>A multicenter molecular epidemiological study was conducted on 653 CREC clinical isolates collected across China (2013–2022), integrated with public genomic data. Pangenome-wide and phylogeographical analyses were performed to uncover recombination events, define the epidemic clone, and trace its evolutionary history. Growth advantage and virulence were evaluated through competition assays and <em>Galleria mellonella</em> infection models.</div></div><div><h3>Results</h3><div>Sequence types (ST) 167, ST410, ST617, and ST361 collectively accounted for 53.8 % (351/653) of the CREC isolates, with ST167 showing a sharp increase in prevalence after 2017. Among these, subclone named <em>Kpn</em>K48 emerged as the primary driver of the increase in ST167 CREC prevalence. Traced to a European origin, <em>Kpn</em>K48 rapidly expanded globally, particularly in China. The remarkable success of <em>Kpn</em>K48 could plausibly be attributed to enhanced survival and virulence, driven by the acquisition of a ∼492 kb recombinant genomic region which mirrored the genomic architecture underlying the hv-CRKP ST11-K64 clone, reflecting a Klebsiella-like evolutionary path. Additionally, plasmid shift in <em>Kpn</em>K48 clone from the prevalent NDM-IncX3 plasmid to Klebsiella-common NDM-IncF plasmid expanded its resistance spectrum and virulence gene repertoire, likely further amplifying its pathogenicity and success.</div></div><div><h3>Conclusions</h3><div>The <em>Kpn</em>K48 subclone combined the features of hypervirulence and carbapenem resistance, bridging genomic traits of <em>E. coli</em> and <em>K. pneumoniae</em>, signifying a broader evolutionary trend with profound global health implications.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101243"},"PeriodicalIF":15.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828746","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 quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML","authors":"Elahe Rahimian ,&nbsp;Masoud Koochak ,&nbsp;Sofia Traikov ,&nbsp;Michael Schroeder ,&nbsp;Silke Brilloff ,&nbsp;Silvia Schäfer ,&nbsp;Vida Kufrin ,&nbsp;Sandra Küchler ,&nbsp;Alexander Krüger ,&nbsp;Peter Mirtschink ,&nbsp;Gustavo Baretton ,&nbsp;Evelin Schröck ,&nbsp;Denis M. Schewe ,&nbsp;Claudia R. Ball ,&nbsp;Martin Bornhäuser ,&nbsp;Hanno Glimm ,&nbsp;Marius Bill ,&nbsp;Alexander A. Wurm","doi":"10.1016/j.drup.2025.101242","DOIUrl":"10.1016/j.drup.2025.101242","url":null,"abstract":"<div><div>Relapse in acute myeloid leukemia (AML) is driven by resistant subclones that survive chemotherapy. It is assumed that these resilient leukemic cells can modify their proliferative behavior by entering a quiescent-like state, similar to healthy hematopoietic stem cells (HSCs). These dormant cells can evade the effects of cytostatic drugs that primarily target actively dividing cells. Although quiescence has been extensively studied in healthy hematopoiesis and various solid cancers, its role in AML has remained unexplored.</div><div>In this study, we applied an HSC-derived quiescence-associated gene signature to an AML patient cohort and found it to be strongly correlated with poor prognosis and active TGF-β signaling. <em>In vitro</em> treatment with TGF-β1 induces a quiescence-like phenotype, resulting in a G0 shift and reduced sensitivity to cytarabine. To find potential therapeutic targets that prevent AML-associated quiescence and improve response to cytarabine, we conducted a comprehensive CRISPR interference (CRISPRi) screen combined with TGF-β1 stimulation. This approach identified TGFBR1 inhibitors, like vactosertib, as effective agents for preventing the G0 shift in AML cell models. However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. To elucidate the underlying mechanism, we performed a multi-faceted approach combining a second CRISPRi screen, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and <em>in silico</em> analysis. Our findings revealed that TGFBR1 inhibitors unintentionally target the nucleoside transporter <em>SLC29A1</em> (ENT1), leading to reduced intracellular cytarabine levels. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101242"},"PeriodicalIF":15.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cTRIP12 counteracts ferroptosis resistance and augments sensitivity to immunotherapy in pancreatic cancer","authors":"Hongyi Lin ,&nbsp;Shuncang Zhu ,&nbsp;Yinhao Chen ,&nbsp;Jinpeng Lu ,&nbsp;Chengke Xie ,&nbsp;Chengyu Liao ,&nbsp;Xiaoxiao Huang ,&nbsp;Ge Li ,&nbsp;Yongding Wu ,&nbsp;Zhiyuan Li ,&nbsp;Jianfei Hu ,&nbsp;Xinquan Lin ,&nbsp;Yifeng Tian ,&nbsp;Qiaowei Li ,&nbsp;Zuwei Wang ,&nbsp;Shi Chen","doi":"10.1016/j.drup.2025.101240","DOIUrl":"10.1016/j.drup.2025.101240","url":null,"abstract":"<div><h3>Aims</h3><div>Current therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) have limited efficacy in increasing patient survival rates, largely due to ferroptosis resistance and immunosuppression. The aim of this study is to identify molecular mechanisms associated with ferroptosis resistance and immunosuppression in PDAC tumour cells.</div></div><div><h3>Methods</h3><div>Circular RNA sequencing (circRNA-seq) was performed on clinical samples to identify potential circRNAs that mediate ferroptosis resistance. C11-BODIPY staining, FerroOrange staining, the glutathione ratio, malondialdehyde quantification, and transmission electron microscopy were employed to assess ferroptosis. RNA pulldown, mass spectrometry, RNA immunoprecipitation, and coimmunoprecipitation assays were conducted to investigate the molecular mechanisms involved. A HuNSG mouse xenograft tumour model was utilized to validate therapeutic agents.</div></div><div><h3>Results</h3><div>A circRNA derived from TRIP12 (cTRIP12) was identified in PDAC samples resistant to ferroptosis. cTRIP12 knockdown increased the sensitivity of PDAC cells to ferroptosis and immunotherapy. Subsequent mechanistic studies revealed that cTRIP12 specifically binds to the O-linked N-acetylglucosamine transferase (OGT) protein and increases intracellular O-GlcNAcylation levels, leading to increased protein levels of ferritin heavy chain (FTH) and PD-L1 in tumour cells. Notably, high cTRIP12 expression suppressed ferroptosis sensitivity and increased immune resistance in PDAC cells by functioning as a protein scaffold through its interaction with OGT and protein kinase R-like endoplasmic reticulum kinase (PERK). cTRIP12 inhibition induced ferroptosis in PDAC cells by reducing FTH and PD-L1 expression and synergistically increased the immunotherapy efficacy. In vivo animal experiments confirmed that the triple therapy consisting of GSK2656157, erastin, and anti-CTLA-4 effectively suppressed the progression of PDAC in tumours with high cTRIP12 expression.</div></div><div><h3>Conclusion</h3><div>We elucidated the molecular mechanisms underlying the simultaneous occurrence of ferroptosis resistance and immune suppression in PDAC patients. Our study provides a novel therapeutic strategy that could promote ferroptosis in tumour cells and increase immunotherapy efficacy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101240"},"PeriodicalIF":15.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers","authors":"Zhu Xu ,&nbsp;Mingming Zhu ,&nbsp;Longpo Geng ,&nbsp;Jun Zhang ,&nbsp;Jing Xia ,&nbsp;Qiang Wang ,&nbsp;Hongda An ,&nbsp;Anliang Xia ,&nbsp;Yuanyuan Yu ,&nbsp;Shihan Liu ,&nbsp;Junjie Tong ,&nbsp;Wei-Guo Zhu ,&nbsp;Yiyang Jiang ,&nbsp;Beicheng Sun","doi":"10.1016/j.drup.2025.101241","DOIUrl":"10.1016/j.drup.2025.101241","url":null,"abstract":"<div><h3>Aims</h3><div>RNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in DSB repair remains largely elusive. In this study, we aim to decipher the role for ac4C modification by NAT10 in DSB repair in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>Laser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used to determine the structures of NAT10 in complex with its inhibitor, remodelin. Hepatocyte-specific deletion of NAT10 mouse models were adopted to detect the effects of NAT10 on HCC progression. Subcutaneous xenograft, human HCC organoid and patient-derived xenograft (PDX) model were exploited to determine the therapy efficiency of the combination of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi) and remodelin.</div></div><div><h3>Results</h3><div>NAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and promotes homologous recombination (HR) repair. The ablation of NAT10 curtails HCC progression. Furthermore, the cryo-EM yields a remarkable 2.9 angstroms resolution structure of NAT10-remodelin, showcasing a C2 symmetric architecture. Remodelin treatment significantly enhanced the sensitivity of HCC cells to a PARPi and targeting NAT10 also restored sensitivity to a PARPi in ovarian and breast cancer cells that had developed resistance.</div></div><div><h3>Conclusion</h3><div>Our study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings suggest that co-inhibition of NAT10 and PARP1 is an effective novel therapeutic strategy for patients with HCC and have the potential to overcome PARPi resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101241"},"PeriodicalIF":15.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685059","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":"Widespread antibiotic heterotolerance in bacteria remains undetected by resistance assays","authors":"Bram Van den Bergh ,&nbsp;Philip Ruelens ,&nbsp;Lieze Agten ,&nbsp;Laurence Van Moll ,&nbsp;Nele Geerts ,&nbsp;Laure Verstraete ,&nbsp;Sang Nguyen ,&nbsp;Linda De Vooght ,&nbsp;Natalie Verstraeten ,&nbsp;Paul Cos ,&nbsp;Jan Michiels","doi":"10.1016/j.drup.2025.101239","DOIUrl":"10.1016/j.drup.2025.101239","url":null,"abstract":"<div><div>Despite global efforts, antimicrobial resistance persists. Mechanisms like heterotolerance further undermine antibiotic effectiveness. Testing &gt; 1000 clinical strains revealed widespread heterotolerance largely missed by conventional MIC-based diagnostics. Since AMR alone does not predict treatment success, new tests and strategies incorporating tolerance data are urgently needed to significantly improve patient outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101239"},"PeriodicalIF":15.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the sulfur-containing amino acid-ROS axis in cancer chemotherapeutic drug resistance","authors":"Bingli Wu ,&nbsp;Yinwei Cheng ,&nbsp;Liyan Li ,&nbsp;Zepeng Du ,&nbsp;Qianlou Liu ,&nbsp;Xinyue Tan ,&nbsp;Xin Li ,&nbsp;Guozhi Zhao ,&nbsp;Enmin Li","doi":"10.1016/j.drup.2025.101238","DOIUrl":"10.1016/j.drup.2025.101238","url":null,"abstract":"<div><div>Chemotherapeutic drug resistance remains a major barrier to effective cancer treatment. Drug resistance could be driven in part by adaptive redox remodeling of cancer cells. Paradoxically, drug-resistant malignancies exhibit elevated reactive oxygen species (ROS), as well as amplified antioxidant defenses, which enable cancer cell survival under therapeutic stress. Central to this adaptation is glutathione (GSH), the predominant cellular antioxidant, whose synthesis relies on sulfur-containing amino acids (SAAs) – methionine and cysteine. This review delineates the metabolic interplay between methionine and cysteine in the transsulfuration pathway, highlighting their roles as precursors in GSH biosynthesis. We systematically summarize the key enzymes that drive GSH production and their contributions to resistance against platinum-based drugs and other chemotherapeutics. In addition to GSH synthesis, we summarize the roles of GSH antioxidant systems, including glutathione peroxidases (GPXs), peroxiredoxins (PRDXs), and thioredoxins (TRXs), which are critical in chemotherapeutic drug resistance through ROS scavenging. Recent advances reveal that targeting these enzymes, by pharmacologically inhibiting transsulfuration enzymes or disrupting GSH-dependent antioxidant cascades, can sensitize resistant cancer cells to ROS-mediated therapies. These findings not only clarify the mechanistic links between SAA metabolism and redox adaptation but also provide practical approaches to overcome chemotherapeutic drug resistance. By analyzing metabolic and redox vulnerabilities, this review highlights the therapeutic potential to restore chemosensitivity, offering new options in precision oncology medicine.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101238"},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642743","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}