Current cancer drug targets最新文献

{"title":"Clinicopathological Profiles and Prognosis of Postoperative HER2-Mutant Non-Small Cell Lung Cancer: A Real-World Analysis.","authors":"Guangjian Yang, Linyan Tian, Xiaoyong Tang, Yan Wang","doi":"10.2174/0115680096450021260709092217","DOIUrl":"https://doi.org/10.2174/0115680096450021260709092217","url":null,"abstract":"<p><strong>Background/introduction: </strong>Patients with non-small cell lung cancer (NSCLC) harboring HER2 mutations remain at high risk of recurrence, even following radical resection for early-stage disease. Currently, there is a paucity of research investigating the clinicopathological characteristics and disease-free survival (DFS) outcomes of this specific postoperative population.</p><p><strong>Methods: </strong>This retrospective study investigated the clinicopathological and molecular characteristics of 77 patients with surgically resected HER2-mutant NSCLC. HER2 mutation status was identified via next-generation sequencing (NGS).</p><p><strong>Results: </strong>HER2 exon 20 insertions were the most prevalent variant in this cohort. Overall, 76.6% of patients exhibited invasive adenocarcinoma phenotypes. Histopathological examination revealed highly invasive papillary and micropapillary components in 51.9% and 45.5% of patients, respectively. The median DFS was 17.0 months (95% CI, 11.4-22.5), with significant variation across disease stages (P = 0.004). The cumulative number of high-risk recurrence factors (0, 1-3, >3) was significantly associated with DFS (median, 29.3 vs. 14.2 vs. 7.1 months; P = 0.045). However, PD-L1 expression status, TP53 alterations, and histological phenotypes demonstrated no significant impact on DFS. Among the entire cohort, 80.5% of patients experienced postoperative recurrence, with the lung being the most frequent site of metastasis.</p><p><strong>Conclusion: </strong>HER2-mutant NSCLC constitutes a distinct subtype characterized by unique clinicopathological and molecular features. For postoperative patients presenting with advanced disease or an increased burden of high-risk recurrence factors, more aggressive therapeutic strategies should be considered.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs and Their Crosstalk with Oncogenic Pathways in Gastric Cancer.","authors":"Liushan Wei, Jia Yu, Yan Hu, Shijie Wu, Yuhui Feng, Shengsong Tang, Guiqin Li, Yuxuan Liang, Xiaoyong Lei, Xiaoyan Yang","doi":"10.2174/0115680096460380260819114647","DOIUrl":"https://doi.org/10.2174/0115680096460380260819114647","url":null,"abstract":"<p><p>Gastric Cancer (GC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer-related mortality worldwide. The aggressive nature of GC, coupled with late clinical presentation and limited therapeutic options, underscores the urgent need for a deeper molecular understanding of its pathogenesis. In the past, microRNAs (miRNAs)-evolutionarily conserved, 19-25-nucleotide, non-protein-coding RNAs-have emerged as pivotal post- transcriptional regulators that simultaneously modulate dozens of messenger RNAs through seed-sequence-mediated binding to 3' untranslated regions. In GC, the most intensively studied axes include Notch, Wnt/β-catenin, Hippo, Hedgehog, TGF-β, MAPK, PI3K-AKT-mTOR, and JAK/STAT. Importantly, these pathways do not operate in isolation; instead, they form interconnected networks wherein a single miRNA can create feed-forward or feedback loops that amplify or attenuate oncogenic signaling. Decoding such miRNA-orchestrated crosstalk is not merely an academic exercise; it offers tangible translational opportunities. Restoration of tumor-suppressive miRNAs using synthetic mimics delivered by lipid nanoparticles, or selective silencing of oncomiRs with antagomirs locked by 2'-O-methoxyethyl modifications, has already shown synergistic efficacy with chemotherapy, HER2-targeted agents, and immune checkpoint blockade in preclinical GC models. Moreover, circulating exosomal miRNA signatures that reflect pathway activation states are being vigorously pursued as minimally invasive biomarkers for early detection, molecular subtyping, and real-time monitoring of therapeutic response. In this comprehensive review, we therefore synthesize current mechanistic insights into miRNA- mediated regulation of the aforementioned signaling highways, highlight context-dependent controversies arising from tumor heterogeneity and microbial influence, and outline rational combinatorial strategies that may accelerate the development of next-generation, highly selective, low-toxicity interventions against gastric cancer.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Identification of Progesterone Receptor Modulators for Breast Cancer through 3D Pharmacophore Screening and MD Simulation of the ChEMBL Database.","authors":"Shiom Mane, Babaso Udugade, Sachinkumar Patil, Poournima Sankpal, Swati Udugade, Talha Jawaid, Ayesha Yasmeen, Rashmi Pathak","doi":"10.2174/0115680096477138260812060120","DOIUrl":"https://doi.org/10.2174/0115680096477138260812060120","url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer remains a major global health concern, creating an urgent need for safer and more effective treatments. This study aimed to identify novel progesterone receptor modulators as potential candidates for targeted breast cancer therapy using an integrated in silico approach.</p><p><strong>Materials and methods: </strong>The X-ray-validated three-dimensional structure of the human progesterone receptor (PDB ID: 7AXK) was refined using PDB-REDO. Ulipristal acetate, aso-prisnil, and mifepristone were selected as reference ligands. Additional structurally similar compounds were identified through SwissSimilarity using the canonical SMILES of ulipristal acetate. A three-dimensional pharmacophore model describing the essential chemical features required for receptor binding was applied to screen compounds from the ChEMBL database. The selected molecules underwent molecular docking to determine their binding affinities and interactions with important receptor residues. ADME-Tox analysis was subsequently conducted to evaluate their drug-likeness, pharmacokinetic properties, and potential toxicity.</p><p><strong>Results: </strong>PDB-REDO refinement improved the overall structural quality of the 7AXK protein, as assessed using Kleywegt's methodology. Docking and pharmacophore screening identified several compounds with strong predicted binding affinities and favourable interactions within the progesterone receptor's binding site. Selected compounds also demonstrated acceptable drug-like properties, promising pharmacokinetic behaviour, and comparatively favourable predicted safety profiles.</p><p><strong>Discussion: </strong>The combined computational strategy effectively identified promising progesterone receptor modulators. These candidates show potential for developing targeted breast cancer treatments; however, molecular dynamics simulations and experimental validation are required.</p><p><strong>Conclusion: </strong>Several potential progesterone receptor modulators with favourable binding and ADME-Tox characteristics were identified. These findings demonstrate the value of computational methods in accelerating early-stage breast cancer drug discovery.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBMC‑secreted Sgp130FcH Inhibits Colorectal Cancer Cells and Cholangiocarcinoma: Proof‑of‑Concept Evidence.","authors":"Khac Cuong Bui, Phuong Linh Thi Nham, Phuong Linh Tran, Dieu Linh Le, Anh Vu Nguyen, Thi Huyen La, Thu Hang Ngo, Przemyslaw Bozko, Hong Ngoc Tham, Quang Huy Nguyen, Linh Toan Nguyen, Mai Ly Thi Nguyen","doi":"10.2174/0115680096489216260818093438","DOIUrl":"https://doi.org/10.2174/0115680096489216260818093438","url":null,"abstract":"<p><p>Introduction/ Objective: IL-6 is associated with carcinogenesis, tumor burden, and poor prognosis in multiple malignancies, including Colorectal Cancer (CRC) and Cholangiocarcinoma (CCA). This study aimed to establish and evaluate the in vitro anti-cancer effect of Peripheral Blood Mononuclear Cell (PBMC)-derived soluble gp130Fc (PBMC Sgp130FcH) on CRC and CCA.</p><p><strong>Methods: </strong>Freshly isolated PBMCs and HCT116 cells were transfected with plasmids encoding Sgp130FcH and hyper-IL-6 (HIL6), respectively. mRNA expression was semi-quantified by RT-qPCR with gene-specific primers. The concentration of Sgp130 in the culture supernatant was measured by ELISA. The anti-cancer effects of PBMC Sgp130FcH, including its effects on cell proliferation, migration, and colony formation, were assessed through direct co-culture with CRC (HCT116) and CCA (TFK1) cell lines.</p><p><strong>Results: </strong>Stable establishment of constitutively activated IL-6 trans-signaling (HCT116 HIL6) and Sgp130FcH-secreting PBMCs (PBMC Sgp130FcH) was achieved. HCT116 HIL6 cells exhibited significantly increased proliferation, migration, and colony formation compared with HCT116 WT (p < 0.05). PBMC Sgp130FcH expressed Sgp130FcH mRNA and secreted high concentrations of Sgp130 ten days after transfection. Compared with PBMC WT, PBMC Sgp130FcH significantly and persistently suppressed proliferation, migration, and colony formation of both CCA and CRC cells in a dose-dependent manner.</p><p><strong>Discussion: </strong>Sustained overexpression of IL-6 trans-signaling in CRC cells promoted a carcinogenic phenotype in vitro. Compared with PBMC WT, PBMC Sgp130FcH showed superior in vitro inhibition on both CRC and CCA cell lines, supporting the functional activity of PBMC-secreted Sgp130FcH as a negative regulator of IL-6 trans-signaling.</p><p><strong>Conclusion: </strong>Our data demonstrate the inhibition of PBMC Sgp130FcH on CRC and CCA cells in vitro, providing preliminary proof-of-concept evidence. Further mechanistic studies and in vivo validation are warranted.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitination-Androgen Receptor Coupling in Prostate Cancer Therapeutics.","authors":"Gali Sri Venkata Sai Rishma Reddy, Krishna Samanta, Pulak Kar","doi":"10.2174/0115680096502346260817094745","DOIUrl":"https://doi.org/10.2174/0115680096502346260817094745","url":null,"abstract":"<p><p>Prostate cancer is one of the most frequently diagnosed malignancies in men and a leading cause of cancer-related mortality worldwide. The androgen receptor (AR) remains the principal driver of prostate cancer progression and castration-resistant prostate cancer (CRPC), with its stability, localization, and transcriptional activity being tightly regulated by the ubiquitin-proteasome system (UPS). E3 ubiquitin ligases and deubiquitinases (DUBs) critically govern AR turnover and signalling output, thereby influencing tumour growth, therapeutic resistance, and disease progression. Emerging evidence further highlights a complex interplay between ubiquitination, DNA damage response (DDR) pathways, and ADP-ribosylation (ADPr) signalling, collectively shaping genomic stability and treatment responsiveness in prostate cancer. This review is organized into four major themes: (i) ubiquitin-mediated regulation of AR signalling, (ii) ubiquitination and DNA damage response in AR-driven prostate cancer, (iii) crosstalk between ubiquitination, ADPr, and AR-associated signalling pathways, and (iv) therapeutic strategies targeting the UPS and AR axis. This study also discusses recent advances in targeted protein degradation, modulation of E3 ligases, inhibition of deubiquitinases, and PARP-based therapeutic approaches. These emerging insights into the interconnected regulation of ubiquitination, AR signalling, DDR pathways, and ADP-ribosylation may facilitate the development of next-generation therapeutic approaches for advanced prostate cancer.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRPL35 Suppresses Autophagy-Mediated Ferroptosis in Hepatocellular Carcinoma via the AMPK/mTOR Axis.","authors":"YuLiang Xu, LiShuai Xiao, ZhiHu Shi, Xi Chen","doi":"10.2174/0115680096518429260818072238","DOIUrl":"https://doi.org/10.2174/0115680096518429260818072238","url":null,"abstract":"<p><strong>Introduction: </strong>Ferroptosis and autophagy are recently identified forms of non-apoptotic regulated cell death with strong therapeutic implications for hepatocellular carcinoma (HCC). Mitochondrial ribosomal protein L35 (MRPL35), a mitochondria- specific component of mitoribosomes, has been proposed as a potential therapeutic target for liver cancer. The study focused on autophagy-dependent ferroptosis in HCC, with an emphasis on the functional significance of MRPL35.</p><p><strong>Methods: </strong>Bioinformatics approaches, RT-qPCR, along with western blotting, were used to determine MRPL35 expression in HCC. CCK-8, scratch, Matrigel, and flow cytometric assays were used to detect cell proliferation, migration, invasion, and apoptosis. JC-1 staining was used to detect mitochondrial function. Assay kits and C11-BODIPY assay were used to detect GSH, GSSG, MDA, ROS, Fe2+, ATP, and lipid ROS levels. MDA staining and western blotting assessed the presence of autophagosomes and autophagy-related proteins. In addition, western blotting was used to detect γ-H2AX, apoptosis-, ferroptosis, and AMPK/mTOR axis-related proteins. The in vivo effects of MRPL35 were confirmed by subcutaneous tumorigenesis assays in nude mice.</p><p><strong>Results: </strong>MRPL35 showed abnormally high expression in HCC with a low survival rate. MRPL35 downregulation suppressed cell viability and metastasis, promoted cell apoptosis and autophagy, as well as ROS-dependent DNA damage, inhibited tumor growth, and promoted ferroptosis and autophagy in HCC-bearing mice. MRPL35 interference also promoted autophagy-mediated ferroptosis. In addition, MRPL35 modulated the AMPK/mTOR axis, and AMPK inhibitor Compound C or AMPKα interference reversed the effects of MRPL35 interference on autophagy-mediated ferroptosis.</p><p><strong>Discussion: </strong>The elucidation of MRPL35's role in mediating the AMPK/mTOR axis is consistent with the well-established pro-tumorigenic role of MRPL35 and the significance of the AMPK/mTOR axis in HCC. The newly characterized MRPL35- AMPK/mTOR axis not only proposes MRPL35 as a therapeutic target for HCC but also advances our understanding of its carcinogenic mechanisms.</p><p><strong>Conclusion: </strong>Overall, a novel regulatory mode of autophagy-reliant ferroptosis was established by the MRPL35/AMPK/mTOR axis in HCC.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmaceutical Potential of Antibody-Drug Conjugate Doublets for Targeted Treatment of Cancers Heterogeneously Expressing RON Receptor Tyrosine Kinase.","authors":"Durga Puro, Sreedhar Reddy Suthe, Hang-Ping Yao, Ming-Hai Wang","doi":"10.2174/0115680096480901260730062525","DOIUrl":"https://doi.org/10.2174/0115680096480901260730062525","url":null,"abstract":"<p><strong>Introduction/background: </strong>Limited RON expression by cancer cells is detrimental for the therapeutic efficacy of Antibody-Drug Conjugates (ADCs). The present study aimed to validate a pharmaceutical strategy of using ADCs in vitro to target cancer cells with RON expression below the therapeutic threshold.</p><p><strong>Materials and methods: </strong>Anti-RON ADCs Zt/g4-MMAE and H5B14-DCM, with distinct epitope-binding properties and different payload-effect mechanisms, were formulated to form anti-RON ADC doublets. Hydrophobic interaction chromatography was used to determine ADC conjugation profile and stability. Flow cytometry was used to study RON internalization. Liquid chromatography-mass spectrometry was used to detect intracellular payload molecules. Various biochemical and biological methods were used to determine cell viability, cell cycle, and cell death.</p><p><strong>Results: </strong>Anti-RON ADC doublets at a 50:50 ratio were effective, with increased efficacy in inducing RON internalization by cancer cells with variable RON expression. This effect increased intracellular payload accumulation, particularly in cells with limited RON expression. Treatment of ADC doublets also caused significant cell cycle arrest, dramatic reductions in cell viability, and increased cell apoptosis. Moreover, cancer cells with limited RON expression responded well to the ADC doublets, exhibiting a dramatic decrease in cell viability and an increase in apoptotic death. Payload synergy within the ADC doublets was responsible for these activities. Finally, the ADC doublets effectively kill cancer cells displaying acquired-payload resistance. This activity was particularly prominent in cancer cells insensitive to ADCs with a single mechanism of action.</p><p><strong>Discussion: </strong>By binding to 2 different antigenic epitopes to deliver 2 payloads possessing different effect mechanisms, anti-RON ADC doublets overcome several shortcomings, such as limited target antigen expression, insufficient target internalization, and acquired payload resistance, observed in anticancer studies following a single ADC treatment.</p><p><strong>Conclusion: </strong>Anti-RON ADC doublets with unique pharmacological features demonstrate enhanced in vitro activity compared to single ADCs, delivering sufficient payloads to achieve cytotoxicity against cancer cells with RON expression below the therapeutic threshold. These findings provide an opportunity to optimize ADC treatment regimens in vivo for cancers expressing low levels of RON.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Omics Integration and Proteomic Annotation Prioritize FAM174BAssociated Monocyte Remodeling in COPD and Lung Adenocarcinoma.","authors":"Hailing Chen, Xuefei Yang, Yufeng Zhao, Huaxin Pang, Ting Huang, Heran Zhou","doi":"10.2174/0115680096496204260803073720","DOIUrl":"https://doi.org/10.2174/0115680096496204260803073720","url":null,"abstract":"<p><strong>Introduction/background: </strong>Chronic obstructive pulmonary disease (COPD) is associated with increased lung adenocarcinoma (LUAD) risk, but the cellular and molecular programs linking chronic inflammatory remodeling to malignancy remain incompletely defined. Transcriptomic overlap alone cannot distinguish potential upstream contributors from downstream remodeling events.</p><p><strong>Materials and methods: </strong>We integrated lung single-cell RNA sequencing datasets from COPD (GSE196638) and LUAD (GSE131907) with two-sample Mendelian randomization (MR) to prioritize shared genes with supportive genetic evidence. Cell-type-resolved transcriptional signatures were identified and intersected across diseases. Shared candidates were screened using cis-eQTL instruments from eQTLGen and GWAS summary statistics for COPD and LUAD. FAM174B protein expression was further examined using publicly available Human Protein Atlas immunohistochemistry data with the anti-FAM174B antibody HPA015306.</p><p><strong>Results: </strong>Intersection analysis identified 484 shared genes enriched in cytoskeletal organization and cell-substrate adhesion. Exploratory MR screening prioritized FAM174B as a leading shared candidate with nominal risk-increasing estimates for COPD (OR = 1.094, 95% CI: 1.009-1.186) and LUAD (OR = 1.196, 95% CI: 1.026-1.395). These estimates should be interpreted as supportive genetic prioritization rather than definitive causal proof, because formal multiple-testing correction and colocalization were not performed. Human Protein Atlas immunohistochemistry showed low FAM174B staining in normal lung tissue and higher staining in lung adenocarcinoma tissue, supporting disease-associated protein expression but not establishing the cellular source within tumor tissue. Single-cell analyses localized FAM174B expression to immune compartments, including monocytes, and ligand-receptor inference suggested LUAD-associated monocyte signaling shifts involving adhesion- and matrix-associated pathways.</p><p><strong>Discussion: </strong>These findings suggest that FAM174B-associated monocyte remodeling may represent a candidate biological context linking COPD-related inflammatory remodeling with LUAD-associated tumor microenvironmental change. However, the evidence remains hypothesis-generating, as the MR analysis was exploratory, the single-cell comparisons were not donor-aware, and protein-level evidence was based on public representative immunohistochemistry images.</p><p><strong>Conclusion: </strong>This integrative analysis prioritizes FAM174B as a shared COPD-LUAD candidate with supportive genetic, single-cell, and protein-level evidence. Experimental validation, colocalization, donor-aware single-cell analysis, and cell-type-resolved protein confirmation are needed before a causal or therapeutic role can be established.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Metal-Dependent Cell Death in Cancer: From Molecular Circuitry to Biomarker-Guided Precision Combination Therapy.","authors":"Xuyang Huang, Xinyue Zhang, Wei Chen, Qi Zhu","doi":"10.2174/0115680096473673260714045019","DOIUrl":"https://doi.org/10.2174/0115680096473673260714045019","url":null,"abstract":"<p><p>Cuproptosis and ferroptosis are increasingly recognised not merely as parallel metal-dependent regulated cell death programmes, but as dynamic state variables of tumour metabolism, redox buffering and immune contexture. In this review, we synthesise the field beyond a descriptive pathway summary. We first integrate the core circuitry that governs death susceptibility, including copper trafficking, mitochondrial protein lipoylation and oxidative phosphorylation, iron handling, polyunsaturated-lipid remodelling, and the glutathione-GPX4/FSP1 antioxidant network. We then critically examine pan-cancer and multi-omics signatures, arguing that transcriptomic scores alone are insufficient to define therapeutic vulnerability without functional state readouts. Preclinical evidence is next reorganised around clinically relevant tasks - reversing drug persistence, radiosensitising resistant tumours, converting immune-cold lesions, and extending opportunities in rare, refractory and paediatric cancers - rather than around pathway labels alone. Particular emphasis is placed on the mechanistic crosstalk between cuproptosis and ferroptosis, the immune consequences of metal-dependent death such as cGAS-STING activation and myeloid remodelling, and the emerging logic of combining metal-death induction with radiotherapy, chemotherapy, immune checkpoint blockade and cellular immunotherapies. Finally, we propose a biomarker-guided translational framework that distinguishes cuproptosis-prone, ferroptosis-prone and state-switching tumours, outlines clinically accessible biomarkers and pharmacodynamic readouts, and positions schedule design, delivery selectivity and systemic-to-tumour toxicity separation as central determinants of success. This perspective reframes metal-dependent cell death from descriptive biology into a deployable precision-oncology strategy.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148807876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HE4 Silence Combined with DDP in the Treatment of Ovarian Cancer, Especially Platinum-resistant Ovarian Cancer.","authors":"Yaxin Zuo, Ruiqin Wang, Yunshu Xu, Xiaodan Zhang, Chunhong Chen, Yanling Gong, Meixing Yan, Dan Hu","doi":"10.2174/0115680096428971260308193220","DOIUrl":"https://doi.org/10.2174/0115680096428971260308193220","url":null,"abstract":"<p><strong>Introduction: </strong>Ovarian cancer (OC) is the most lethal gynecological malignancy. Human epididymis protein 4 (HE4) is a secreted glycoprotein serving as a clinical OC biomarker. This study aimed to employ RNAi technology to silence HE4 gene expression, combined with cisplatin (DDP), to explore the effects on the OVCAR-3 cell line and its cisplatin-resistant counterpart.</p><p><strong>Methods: </strong>The cisplatin-resistant cell line OVCAR-3/DDP was established via stepwise dose escalation. RT-qPCR and Western blot were used to detect the expression of HE4, JAK2, STAT3, and ERK1/2 genes and proteins in HOSEpiC, OVCAR-3, and OVCAR-3/DDP. The effects of HE4 siRNA combined with cisplatin on the proliferation, migration, invasion, and apoptosis of OC cells were evaluated, and the effects on gene and protein expression in cells were detected.</p><p><strong>Results: </strong>HE4 was significantly upregulated in OVCAR-3, especially in OVCAR-3/DDP. Knockdown of HE4 inhibited the proliferation, migration, and invasion of OC cells, promoted cell apoptosis, and increased the sensitivity of drug-resistant cells to DDP. The combined application of HE4 siRNA and DDP was more effective than single-drug treatment. Mechanistically, knockdown of HE4 reduced the mRNA levels of JAK2, STAT3, ERK1/2, and the phosphorylation levels of their proteins. suggesting involvement of these pathways. However, the synergy with cisplatin likely also involves constraining cancer cell plasticity, a key adaptive resistance mechanism.</p><p><strong>Discussion: </strong>Platinum-resistant OC has limited treatment options, posing a major clinical challenge. HE4 siRNA, especially when combined with DDP, shows therapeutic potential for OC, particularly platinum-resistant OC-this is linked to the inhibition of JAK/STAT3 and ERK1/2 signaling after HE4 silencing. Future research should clarify pathway-related genes to deepen the understanding of HE4's mechanisms in OC. Additionally, optimizing the delivery strategy of HE4 siRNA remains a key focus for its clinical translation.</p><p><strong>Conclusion: </strong>HE4 may regulate tumor progression and drug resistance by activating the JAK/STAT and MAPK pathways, holding promise as a new target for OC treatment. The combined application of HE4 siRNA and DDP may provide a new treatment option for OC.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}