Drug Resistance Updates最新文献

{"title":"Defining homologous recombination deficiency status in pancreatic ductal adenocarcinoma: Clinical implications for evaluating response to platinum chemotherapy","authors":"Yanxia Wang ,&nbsp;Fancheng Kong ,&nbsp;Xiaohua Situ ,&nbsp;Tiantian Yang ,&nbsp;Tianqi Sun ,&nbsp;Zhongpeng Xie ,&nbsp;Pingling Wang ,&nbsp;Yu Chen ,&nbsp;Neng Jiang ,&nbsp;Yu Dong ,&nbsp;Zhaofan Luo ,&nbsp;Zunfu Ke","doi":"10.1016/j.drup.2025.101291","DOIUrl":"10.1016/j.drup.2025.101291","url":null,"abstract":"<div><h3>Aims</h3><div>Pancreatic ductal adenocarcinoma (PDAC) remains a daunting malignancy with limited therapeutic options; effective biomarkers are needed to improve its treatment decision-making. The aim of this study is to evaluate the role of homologous recombination deficiency (HRD) in assessing the response to platinum chemotherapy in PDAC.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted on 264 patients diagnosed with PDAC. Tumor tissue samples were subjected to next-generation sequencing (NGS) to assess DNA damage repair (DDR) gene mutation landscape and HRD score. The integrated HRD score was calculated as the unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST) scores. The associations between HRD status and clinical outcomes in patients receiving platinum treatment were systematically analyzed.</div></div><div><h3>Results</h3><div>Patients with <em>BRCA1/2</em> biallelic loss-of-function (BILOF) status and/or an HRD score ≥ 42 were predefined as HRD-positive. According to this HRD status definition, 4.9 % (n = 13) of the 264 patients were identified as HRD-positive, identifying a broader population than using <em>BRCA1/2</em> BILOF alone (1.9 %, n = 5). Patients with <em>BRCA1/2</em> mutations (<em>BRCA1/2 </em>^m), presented a lower frequency of alteration in genes related to non-homologous end joining (NHEJ) and mismatch repair (MMR) genes than those with <em>BRCA1/2</em> wild-type (<em>BRCA1/2 </em>^wt), with mutations observed in 46.15 % (6/13) of <em>BRCA1/2 </em>^m versus 72.91 % (183/251) of <em>BRCA1/2 </em>^wt patients. The median HRD score (23) in patients with DNA damage repair (DDR) gene BILOF mutations was notably higher than that in those with non-BILOF mutations in DDR genes (9). HRD-positive patients demonstrated markedly longer progression-free survival (PFS) (median PFS 44.1 months) than HRD-negative patients (median PFS 12.2 months) when the patients received first-line platinum-based adjuvant treatment (<em>P</em> = 0.035). Specifically, patients with <em>BRCA1/2</em> BILOF exhibited a substantial clinical benefit from platinum therapy, with none of these patients experiencing disease progression or death during follow-up.</div></div><div><h3>Conclusions</h3><div><em>BRCA1/2</em> BILOF plays a crucial role in identifying PDAC patients for first-line platinum-based adjuvant treatment, and HRD positive status, defined by <em>BRCA1/2</em> BILOF and/or an HRD score ≥ 42, broadens the pool of eligible patients, and helps avoid ineffective treatment due to intrinsic drug resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101291"},"PeriodicalIF":21.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879766","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 delivery challenges of antimicrobial peptides for clinical translation: From nanocarriers to molecular modifications","authors":"Nan Gao,&nbsp;Jiaqi Sun,&nbsp;Xiang Li,&nbsp;Yuting Yao,&nbsp;Yujie Hu,&nbsp;Jiani Zhao,&nbsp;Anshan Shan,&nbsp;Jiajun Wang","doi":"10.1016/j.drup.2025.101289","DOIUrl":"10.1016/j.drup.2025.101289","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) have emerged as a promising solution to combat multidrug-resistant (MDR) bacteria. Their unique mechanisms of action reduce the likelihood of resistance development. However, despite their potential, AMPs in clinical trials face significant challenges, including proteolytic degradation and short half-lives during systemic or oral administration. To address these limitations and enhance AMP stability and therapeutic efficacy, several key strategies have been explored. In this review, we summarize recent advances in AMP design, covering: 1) the delivery and formulation of AMPs, including metal-based, polymer-based, and lipid-based delivery systems, as well as the self-assembled nanotechnology of AMPs; 2) the internal modification of AMPs, including stereochemical modification, structural cyclization modification, and terminal modification. This review provides critical insights into AMP optimization, guides the development of future drug candidates, and highlights the interdisciplinary approaches required to accelerate clinical translation.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101289"},"PeriodicalIF":21.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809211","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":"Targeting DNA damage response pathways in tumor drug resistance: Mechanisms, clinical implications, and future directions","authors":"Hengzhou Zhu ,&nbsp;Yuanyang Tian ,&nbsp;Haoyan Chen ,&nbsp;Yiyang Qian ,&nbsp;Jiahui Li ,&nbsp;Dong Niu ,&nbsp;Wenyue Zhao ,&nbsp;Yulin Wu ,&nbsp;Xian Zhang ,&nbsp;Tao Tang ,&nbsp;Hu Li ,&nbsp;Yan-Fang Xian ,&nbsp;Dongdong Sun ,&nbsp;Chunhui Jin","doi":"10.1016/j.drup.2025.101287","DOIUrl":"10.1016/j.drup.2025.101287","url":null,"abstract":"<div><div>Targeting DNA damage response (DDR) pathways has become a promising strategy for overcoming tumor drug resistance, particularly in cancers with DNA repair defects. DDR pathways, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR), are essential for maintaining genomic stability. However, resistance to DDR-targeted therapies, such as PARP inhibitors, often arises due to tumor adaptation through various mechanisms. These include HR pathway restoration, mutations in DDR proteins, altered drug metabolism, and the activation of compensatory repair pathways. This review provides a comprehensive analysis of the molecular mechanisms underlying DDR resistance in tumors and explores the clinical implications of these mechanisms in the context of ongoing therapeutic strategies. We also discuss emerging approaches to overcome DDR resistance, including the development of novel DDR inhibitors, combination therapies, and precision medicine approaches based on biomarkers. Furthermore, we highlight future research directions, focusing on the use of advanced technologies, such as CRISPR screening, single-cell sequencing, and artificial intelligence, to uncover new targets and therapeutic strategies to combat DDR-related drug resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101287"},"PeriodicalIF":21.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809388","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":"Drug resistance in breast cancer: Mechanisms and strategies for management","authors":"Guo-Yu Wu ,&nbsp;Ming-Zhu Xiao ,&nbsp;Wei-Chao Hao ,&nbsp;Zhao-Shou Yang ,&nbsp;Xin-Ran Liu ,&nbsp;Dian-Shuang Xu ,&nbsp;Zhong-Xing Peng ,&nbsp;Lu-Yong Zhang","doi":"10.1016/j.drup.2025.101288","DOIUrl":"10.1016/j.drup.2025.101288","url":null,"abstract":"<div><div>Therapeutic resistance remains a significant challenge in breast cancer treatment, often driven by factors such as genetic mutations, dysregulation of receptors and signaling pathways, alterations in drug metabolism and transport, cellular heterogeneity, and modifications in the tumor microenvironment. As a highly heterogeneous and complex disease, breast cancer exhibits distinct molecular and histopathological characteristics, necessitating tailored therapeutic approaches. This article reviews recent advancements in understanding therapy resistance across four major subtypes — Luminal A, Luminal B, HER2-enriched, and triple-negative breast cancer (TNBC) — and explores potential strategies to overcome resistance, providing insights into developing novel therapeutic interventions. Notably, TNBC patients have limited treatment options, with chemotherapy remaining the standard approach and immunotherapy emerging as an adjunct strategy. We concisely overview key mechanisms contributing to therapy resistance and discuss innovative therapeutic strategies, including combination regimens, molecularly targeted therapies, photodynamic therapy, and ferroptosis-inducing treatments. Additionally, we highlight recent advancements in multi-omics data integration and artificial intelligence-driven approaches in breast cancer research. Future efforts should focus on refining predictive models, optimizing combination therapies, and leveraging artificial intelligence to enhance treatment efficacy, ultimately overcoming resistance and improving long-term outcomes for breast cancer patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101288"},"PeriodicalIF":21.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809389","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":"Targeted therapy in acute myeloid leukemia: Resistance and overcoming strategy","authors":"Feifeng Song ,&nbsp;Sisi Lin ,&nbsp;Tong Xu ,&nbsp;Chang Yang ,&nbsp;Bold Sharavyn ,&nbsp;Hua Naranmandura ,&nbsp;Yiwen Zhang ,&nbsp;Ping Huang","doi":"10.1016/j.drup.2025.101286","DOIUrl":"10.1016/j.drup.2025.101286","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid blasts, leading to hematopoietic suppression and bone marrow failure. Advances in understanding the pathogenesis of AML have fueled the development of precision medicine approaches, with notable successes in targeting specific mutant proteins (e.g., FLT3, IDH1, IDH2), apoptotic regulators (e.g., BCL-2, MCL1), and cell-surface antigens (e.g., CD33, CD123, CD47). These targeted inhibitors exhibit moderate antileukemic activity as monotherapies and their clinical responses are often limited due to the emergence of drug resistance and disease relapse. Nevertheless, synergistic effects have been observed when these agents are combined with conventional chemotherapy or oncogenic pathway inhibitors. This review analyzes the current limitations of targeted therapies and explores multifaceted resistance drivers, encompassing on-target mutations, compensatory signaling pathway activation, drug-efflux mechanisms mediated by metabolic enzymes or transporters, intrinsic adaptive changes, and interactions with the tumor microenvironment. Corresponding therapeutic counterstrategies are also examined, such as mutation-specific molecular targeting, combinatorial suppression of alternative pathways, disruption of intrinsic adaptive responses, and immunotherapeutic approaches. These evolving interventions aim to overcome specific resistance mechanisms and reduce relapse rates. Future research integrating these strategies holds significant promise for addressing persistent challenges in AML management, ultimately advancing treatment paradigms and patient survival.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101286"},"PeriodicalIF":21.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781257","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":"Emerging role of sialylation in cancer therapy resistance: Mechanisms and therapeutic implications","authors":"Rebecca E. Farrell ,&nbsp;Kell A. Stelzer ,&nbsp;Guo-Jun Liu ,&nbsp;Danielle Skropeta","doi":"10.1016/j.drup.2025.101285","DOIUrl":"10.1016/j.drup.2025.101285","url":null,"abstract":"<div><div>Resistance to existing cancer therapies is a major factor contributing to cancer's persistence as a global health challenge. Abnormal sialylation patterns, commonly due to changes in the expression of sialyltransferases (STs) is a well-established property of tumour cells. There is a growing body of evidence to demonstrate that sialylation is involved in resistance to chemotherapy, targeted therapy, radiotherapy and immunotherapy through a variety of mechanisms that are still being unveiled. In this review, we summarise the reported correlations between aberrant sialylation and cancer therapy resistance, the underlying mechanisms discovered thus far, and progress made in targeting sialylation to enhance responsiveness to cancer treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101285"},"PeriodicalIF":21.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781258","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":"Engineering nanoplatforms of bacterial outer membrane vesicles to overcome cancer therapy resistance","authors":"Qing-Qing Chai ,&nbsp;Dan Li ,&nbsp;Min Zhang ,&nbsp;Yong-Wei Gu ,&nbsp;Ai-Xue Li ,&nbsp;Xin Wu ,&nbsp;Xiao-Yan Liu ,&nbsp;Ji-Yong Liu","doi":"10.1016/j.drup.2025.101277","DOIUrl":"10.1016/j.drup.2025.101277","url":null,"abstract":"<div><div>Resistance to cancer therapy is driven by physical barriers, tumor heterogeneity, selective therapeutic pressure, immunosuppressive tumor microenvironment (TME) and others. Bacterial outer membrane vesicles (OMVs) represent a promising nanotherapeutic platform to combat cancer therapy resistance. This review discusses the dual roles of OMVs in tumorigenesis and cancer therapy, highlighting their potential applications to enhance treatment efficacy. OMVs from pathogenic bacteria, such as <em>Fusobacterium nucleatum</em> and <em>Helicobacter pylori</em>, exacerbate chemoresistance by reshaping TME through hypoxia-induced metabolic reprogramming and immune evasion, while OMVs from some bacteria, such as probiotics, counteract immunosuppression by promoting cytotoxic T-cell infiltration and macrophage polarization. As bio-derived and conveniently engineered drug delivery platforms, OMVs maximize the synergetic anticancer effect by pathogen associated molecular patterns and the payloads. These functional payloads include siRNAs, cytotoxicity and molecular agents, and immune checkpoint inhibitors. Bacterial OMVs demonstrate unique advantages through their capacity to penetrate physical barriers, achieve tumor-specific targeting, activate immune responses, to overcome cancer therapy resistance. A successful example is the OMV-based nanoplatform with engineered OMVs co-delivering CD47-siRNA and doxorubicin to overcome drug resistance by inducing immunogenic cell death and dendritic cell activation of glioblastoma. Furthermore, OMV-based cancer vaccines presented with tumor antigens or hybridized with tumor-derived membranes enhance dendritic cell maturation and antigen-specific T-cell responses, reversing treatment resistance. By addressing challenges in mass production and safety concerns, OMVs-based platforms can be developed as powerful tools for more effective and personalized cancer treatments.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101277"},"PeriodicalIF":15.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665099","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":"EMT and cancer stem cells: Drivers of therapy resistance and promising therapeutic targets","authors":"Mingyang Jiang ,&nbsp;Jinlong Wang ,&nbsp;Yize Li ,&nbsp;Ke Zhang ,&nbsp;Tao Wang ,&nbsp;Zhandong Bo ,&nbsp;Shenyi Lu ,&nbsp;Raquel Alarcón Rodríguez ,&nbsp;Ruqiong Wei ,&nbsp;Mingtao Zhu ,&nbsp;Christophe Nicot ,&nbsp;Gautam Sethi","doi":"10.1016/j.drup.2025.101276","DOIUrl":"10.1016/j.drup.2025.101276","url":null,"abstract":"<div><div>Cancer continues to be a primary cause of death, resulting in substantial mortality and illness globally. It remains a significant global health issue, greatly affecting morbidity and mortality across the world. Therapeutic resistance poses a major challenge to cancer treatments, acting as a significant barrier to the effectiveness of both standard and targeted therapies. This resistance develops through various mechanisms that allow tumor cells to adapt to and escape the damaging effects of chemotherapy, radiation, and targeted therapies. Ultimately, this leads to disease recurrence and progression. This review examines the dual roles of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in promoting chemoresistance and metastasis. EMT is a dynamic and reversible biological process in which epithelial cells acquire mesenchymal characteristics, increasing their invasiveness and resistance to programmed cell death. CSCs are a subset of cancer cells with the ability to self-renew and play a crucial role in tumor relapse and resistance to treatment. EMT and CSCs are closely interconnected, collaboratively enhancing cancer cell plasticity, metastatic ability, and treatment resistance. The initiation of EMT in cancer cells can generate a CSC-like population, which promotes tumor recurrence and spread. This interaction highlights the importance of targeting both EMT and CSC pathways to develop more effective treatment strategies that address treatment resistance and prevent metastasis. Promising approaches include using natural substances, small molecules, and nanotechnology to block critical signaling pathways and interfere with resistance mechanisms. A more thorough understanding of the molecular factors underlying EMT and CSC plasticity is crucial for crafting personalized treatments that target tumor heterogeneity and improve clinical outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101276"},"PeriodicalIF":21.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725039","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":"Hypoxia-induced upregulation of HIF1A-AS3 promotes MSC transition to cancer-associated fibroblasts and confers drug resistance in gastric cancer","authors":"Jiajin Xu ,&nbsp;Shuo Fang ,&nbsp;Xiaotong Dong ,&nbsp;Chengdong Liang ,&nbsp;Ruoyu Yang ,&nbsp;Yang Zhao ,&nbsp;Hailong Gu ,&nbsp;Min Fu ,&nbsp;Jiahui Zhang ,&nbsp;Xiaoxin Zhang ,&nbsp;Xu Zhang ,&nbsp;Runbi Ji","doi":"10.1016/j.drup.2025.101275","DOIUrl":"10.1016/j.drup.2025.101275","url":null,"abstract":"<div><div>Chemotherapy resistance is a major cause of poor prognosis in gastric cancer patients and tumor microenvironment plays a critical role in conferring chemotherapy resistance. As a dominant source of tumor stromal cells, mesenchymal stem cells (MSCs) exert pro-oncogenic activities when reprogrammed to a cancer-associated fibroblast (CAF) phenotype. The precise mechanisms for MSC reprogramming and their subsequent role in chemotherapy resistance have not been fully understood. Herein, we reported that HIF1A-AS3, a lncRNA that was highly expressed in tumor-promoting MSCs, was upregulated in tumor tissues and serum of gastric cancer patients and associated with poor prognosis. The upregulation of HIF1A-AS3 reprogramed MSCs to acquire the CAF phenotype, which consequently enhanced the resistance of gastric cancer cells to oxaliplatin. Mechanistically, hypoxia related transcription factor HIF-1α induced high expression of HIF1A-AS3 in MSCs. Then, HIF1A-AS3 competitively sponged miR-142–3p and miR-24–3p, leading to the upregulation of PROX1 (prospero-related homeobox protein 1) gene expression. This further promoted the nuclear translocation of β-catenin and the activation of β-catenin signaling pathway in MSCs, which critically regulated their transition to CAFs. Finally, targeted inhibition of HIF1A-AS3 in hypoxia-MSCs through exosome-mediated siRNA delivery significantly suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Conclusively, hypoxia-induced HIF1A-AS3 upregulation reprograms MSCs to CAFs through the miR-142–3p/miR-24–3p/PROX1/β-catenin axis, thereby promoting chemotherapy resistance in gastric cancer, which uncovers a new molecular mechanism for MSCs transition to CAFs in gastric cancer and provides a new target for the diagnosis and targeted therapy of gastric cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101275"},"PeriodicalIF":15.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665096","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":"ZNF207-driven PRDX1 lactylation and NRF2 activation in regorafenib resistance and ferroptosis evasion","authors":"Tianfeng Yang ,&nbsp;Suyu Zhang ,&nbsp;Kun Nie ,&nbsp;Cheng Cheng ,&nbsp;Xiuhong Peng ,&nbsp;Jian Huo ,&nbsp;Yanmin Zhang","doi":"10.1016/j.drup.2025.101274","DOIUrl":"10.1016/j.drup.2025.101274","url":null,"abstract":"<div><div>Regorafenib (RGF) is a critical second-line therapy for advanced hepatocellular carcinoma (HCC) following disease progression on sorafenib; however, the rapid onset of RGF resistance poses a significant barrier to enhancing patient outcomes. In this study, CRISPR/Cas9 screening in RGF-treated HCC cells identified Zinc Finger Protein 207 (ZNF207) as a primary driver of resistance. Further analysis revealed that ZNF207 promotes resistance by inducing antioxidant responses that inhibit ferroptosis, a form of iron-dependent cell death. Mechanistically, ZNF207 facilitates the lactylation of peroxiredoxin 1 (PRDX1) at lysine 67, enhancing nuclear translocation and activation of nuclear factor erythroid 2–related factor 2 (NRF2), a master regulator of antioxidant pathways. This ZNF207-PRDX1-NRF2 pathway creates a ferroptosis-resistant, pro-survival environment under RGF treatment, enabling HCC cells to evade cell death. Functional assays demonstrated that ZNF207 knockdown significantly enhances RGF sensitivity by restoring ferroptosis, with additional findings showing that disrupting PRDX1 lactylation or NRF2 activity similarly reverses resistance. Together, these findings establish a critical link between protein lactylation and RGF resistance, positioning the ZNF207-PRDX1-NRF2 axis as a promising therapeutic target to enhance treatment efficacy in HCC. The implications of this research extend beyond HCC, indicating that targeting ferroptosis-suppressive pathways may offer a broader approach to overcoming resistance in various cancers.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101274"},"PeriodicalIF":15.8,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144613303","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}