Clinical and Experimental Medicine最新文献

{"title":"Machine learning-based identification of lactate metabolism-associated biomarkers in non-alcoholic fatty liver disease.","authors":"Xiaocui Wang, Xinhan Wang, Liang Zhao, Li Song","doi":"10.1007/s10238-026-02250-z","DOIUrl":"10.1007/s10238-026-02250-z","url":null,"abstract":"<p><p>To determine lactate metabolism-associated biomarkers for non-alcoholic fatty liver disease (NAFLD). Based on NAFLD datasets from the gene expression omnibus database and lactate metabolism-related genes from GeneCards database, NAFLD-lactate metabolism hub genes (NAFLD-LM HGs) were screened via differential analysis, weighted gene co-expression network analysis and four machine learning algorithms. Their diagnostic efficacy was evaluated; molecular subtyping was performed; single-cell RNA sequencing (scRNA-seq) was subsequently conducted; and validation was finally conducted in NAFLD mouse models. We finally screened out eight NAFLD-LM HGs, namely CCAAT/enhancer-binding protein alpha (CEBPA), flavin containing dimethylaniline monooxygenase 1 (FMO1), insulin-like growth factor-binding protein 1 (IGFBP1), krüppel-like factor 4 (KLF4), low-density lipoprotein receptor (LDLR), myelocytomatosis oncogene (MYC), nuclear receptor subfamily 4 group A member 2 (NR4A2), and thymidylate synthase (TYMS), with a diagnostic rate of 0.798 and an area under the curve of 0.948. These genes drove the molecular heterogeneity in NAFLD patients by modulating of metabolism and immune microenvironment. The results of scRNA-seq clarified that Th17 cells were identified as the most abundant annotated cell subset. Through animal experiments, five genes (LDLR, MYC, IGFBP1, NR4A2, and KLF4) were established to have potential protective effects against NAFLD. Five genes (LDLR, MYC, IGFBP1, NR4A2, KLF4) are identified as \"protective factors\", and their downregulation is associated with NAFLD progression. The remaining three genes (CEBPA, FMO1, TYMS) exhibit inconsistent expression patterns, suggesting bidirectional regulation.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CK2 in triple-negative breast cancer: oncogenic signaling networks and emerging CK2 inhibitor-based combination therapies.","authors":"Navas Shereef Ellyan, Angel Treasa Alex, Usha Yogendra Nayak, Alan Raj, Rahul K","doi":"10.1007/s10238-026-02256-7","DOIUrl":"10.1007/s10238-026-02256-7","url":null,"abstract":"<p><p>The aggressive and highly heterogeneous subtype of breast cancer, triple-negative breast cancer (TNBC), has a poor response to conventional treatments and a high propensity for metastasis, causing unfavorable clinical outcomes. In TNBC, casein kinase 2 (CK2), a constitutively active serine/threonine kinase, plays a key role in controlling several oncogenic signaling pathways. Aberrant CK2 signaling promotes increased transcription of oncogenes, proliferative signaling, DNA repair, epigenetic regulation, epithelial-to-mesenchymal transition (EMT), and cancer stem cell maintenance. Additionally, CK2 helps maintain tumor redox homeostasis by regulating the balance of zinc and copper and by stabilizing immunological checkpoint proteins such as PD-L1. Due to its pleiotropic effects, CK2 overactivation promotes treatment resistance across TNBC subtypes and accelerates tumor growth. Pharmacological inhibition of CK2 can disrupt these communication networks, making TNBC cells more susceptible to both traditional and targeted treatments. By concurrently suppressing compensatory survival mechanisms, CK2 inhibitors have demonstrated synergistic anticancer benefits when used with chemotherapy, PI3K/AKT/mTOR inhibitors, PARP inhibitors, and immunotherapies. This study highlights the complex role of aberrant CK2 signaling in TNBC progression and examines the therapeutic promise of CK2 inhibitor-based combination therapies to overcome resistance and improve treatment efficacy. Current preclinical and clinical research on next-generation CK2 inhibitors highlights their potential as a novel therapeutic approach for TNBC.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Von Willebrand, factor VIII, and D-dimer levels as predictors of risk and clinical outcomes in acute myeloid leukemia.","authors":"Hanaa Ali El-Sayed, Doaa H Sakr, Mohamed Awad Ebrahim, Reham Alghandour, Eman Eid, May Denewer, Balvinder Saarsalu, Maha Othman, Hanan Azzam","doi":"10.1007/s10238-026-02198-0","DOIUrl":"10.1007/s10238-026-02198-0","url":null,"abstract":"<p><p>Coagulopathies, infection, and CNS infiltration are common complications during induction therapy of acute myeloid leukemia (AML). Early identification of adverse-risk patients may improve outcomes. This study evaluated the predictive value of coagulation markers, von Willebrand Factor antigen (vWF-ag), von Willebrand Factor-ristocetin cofactor (vWF-RCof), antihemophilic factor (FVIII), and D-dimer on risk stratification, severity and outcomes of AML patients. Fifty AML patients treated at Oncology Center Mansoura University hospital, from February 2023 to February 2024 were recruited and stratified into three risk groups favourable, intermediate, and adverse risk groups respectively according to the 2022 European leukemianet (ELN) risk stratification for AML. vWF-ag, vWF: RCof, FVIII, and D-dimer were measured at diagnosis and at remission. Adverse-risk group had the highest median levels of vWF-ag, vWF-RCof, FVIII and D-dimer at, both diagnosis and remission (p < 0.05). All markers significantly declined after remission (p < 0.05). vWF-ag, vWF-RCof, and D-dimer differed significantly among risk groups at both diagnosis and remission. ROC analysis showed that in the adverse-risk group, D-dimer had an AUC of 0.813 (cutoff > 1.6), vWF: Ag 0.780 (> 295), and vWF: RCo 0.761 (> 223). FVIII showed lower predictive value (AUC 0.625). Infection was the most frequent complication, followed by bleeding and thrombosis. Infection correlated with higher vWF: Ag after remission; thrombosis correlated with elevated vWF: Ag at diagnosis and remission and bleeding with lower vWF-ag. CNS infiltration showed no association. vWF-ag, vWF-RCof, and D-dimers may be associated with risk and complications in AML, but these findings require external validation in larger cohorts.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropeptide Y promotes myocardial fibrosis post myocardial infarction reperfusion through Neuropeptide Y receptor type 1.","authors":"Dinghui Wang, Bo Wei, Chunfeng Cao, Yali Xu, Wen Gou","doi":"10.1007/s10238-026-02253-w","DOIUrl":"10.1007/s10238-026-02253-w","url":null,"abstract":"<p><p>Although the treatment of ischemic heart disease is becoming increasingly mature, the role of neuropeptide Y (NPY) in the pathophysiology after reperfusion still remains remains unanswered. In our study, we used a mouse model of myocardial ischemia/reperfusion (I/R) injury and demonstrated significant upregulation of NPY and its receptor NPYR1 after reperfusion. Over-expression of NPYR1exacerbates cardiac remodeling, manifested as worsening myocardial fibrosis (p < 0.01) and impaired left ventricular ejection fraction. On the contrary, NPYR1 knockdown weakened fibrosis response and improved cardiac function recovery. These findings were confirmed in HL-1 cell line subjected to hypoxia/reoxygenation model, where fibrotic markers of cardiomyocyte were similarly influenced by NPYR1 modulation. Our research findings indicate that NPY/NPYR1 signaling plays a pivotal role in maladaptive cardiac remodeling post I/R injury and is a promising therapeutic target for alleviating excessive fibrosis.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ncRNA-driven regulation of PD-L1 in breast cancer: mechanisms of immune escape and therapeutic opportunities.","authors":"Amirhossein Mardi, Sajjad Rajabi Moghaddam, Ali Roohi Motlagh, Amirreza Mehmandar-Oskuie","doi":"10.1007/s10238-026-02252-x","DOIUrl":"10.1007/s10238-026-02252-x","url":null,"abstract":"<p><p>Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule important in tumor immune evasion acting primarily by inhibiting T cell activation. In breast cancer, PD-L1 is frequently abnormally expressed and associated with tumor progression, metastasis, and poor prognosis. Recent studies have revealed that non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are important post-transcriptional regulators of PD-L1. ncRNAs regulate PD-L1 expression through multiple mechanisms, including direct binding to PD-L1 mRNA 3' UTR, acting as competing endogenous RNAs (ceRNAs), altering transcription factor activity, and altering epigenetic modifications. Dysregulation of ncRNAs not only impact PD-L1-mediated immune escape (i.e., cancer immune evasion), but can also remodel the tumor microenvironment (TME) through impact on immune cell infiltration and activity, and alterations to cytokine production. This review provides an overview of current understanding of ncRNAs regulating PD-L1 in breast cancer, specifically their molecular mechanisms, therapeutic potential, and clinical relevance as biomarkers and/or therapeutic targets. The broad ncRNA-PD-L1 regulatory network is complex, and discoveries in this field may create novel avenues for precision immunotherapy and combination strategies in treating breast cancer.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating microRNAs as prognostic biomarkers in patients with oropharyngeal cancer undergoing radiotherapy: temporal dynamics analysis.","authors":"Bartłomiej Tomasik, Damian Mikulski, Bartosz Kamil Sobocki, Kasper Kuna, Anna Papis-Ubych, Konrad Stawiski, Jacek Burzyński, Jacek Fijuth, Piotr Kędzierawski, Jacek Sadowski, Rafał Stando, Robert Bibik, Łukasz Graczyk, Tomasz Latusek, Tomasz Rutkowski, Wojciech Fendler","doi":"10.1007/s10238-026-02237-w","DOIUrl":"https://doi.org/10.1007/s10238-026-02237-w","url":null,"abstract":"<p><p>The incidence of oropharyngeal cancer (OPC) is increasing. Thus, there is a need for biomarkers that can identify high-risk patients and support personalised treatment. This study investigated the prognostic significance of circulating microRNAs (miRNAs) for progression-free survival (PFS) and overall survival (OS) in patients with OPC undergoing radiotherapy (RT). The expression of 20 circulating miRNAs was analysed in serum samples collected both before and after RT as a possible prognostic marker in patients treated for OPC. We analysed 80 patients with OPC treated with curative-intent RT. The median PFS was 42.9 months (95%CI: 25.6 - not reached), and the median OS was 63.7 months (95%CI: 33.9 - not reached). In univariate analysis, higher pre-treatment levels of miR-21-5p (HR: 2.12, 95%CI: 1.34-3.36) and miR-148a-3p (HR: 1.38, 95%CI: 1.03-1.85), as well as lower post-treatment levels of miR-345-5p (HR: 0.61, 95%CI: 0.41-0.90), were associated with worse survival. These associations remained significant in multivariable analysis adjusted for clinical factors. A combined risk model based on pre-RT miR-21-5p and post-RT miR-345-5p identified a high-risk group with significantly shorter PFS (HR: 3.01, 95%CI: 1.27-7.14) and OS (HR: 3.19, 95%CI: 1.25-8.15) compared with the low-risk group. High pre-RT hsa-miR-21-5p and low post-RT hsa-miR-345-5p were both independently associated with inferior PFS and OS. These results support the clinical relevance of integrating dynamic miRNA profiling into risk-stratification frameworks and may potentially inform more personalised strategies for post-RT monitoring in OPC patients.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497224","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":"Research progress on the regulation of mesothelioma driven by deubiquitinating enzyme BAP1.","authors":"Wan-Ting Xuan, Yao Dong, Si-Yuan Ma, Man Liu, Xiao-Qi Liu, Na-Na Yao, Lan-Xi Hu, Ling-Ling Shi, Lin Ma, Jing-Hui Bai, Bo Huang","doi":"10.1007/s10238-026-02249-6","DOIUrl":"10.1007/s10238-026-02249-6","url":null,"abstract":"<p><p>Mesothelioma is a highly aggressive malignancy that develops through the combined influence of several factors, including environmental exposure, genetic susceptibility, immune status, and aberrant activation or dysregulation of signaling pathways. The BAP1 gene, a tumor suppressor located at chromosome 3p21.1, plays a pivotal role in maintaining genomic stability by functioning as a deubiquitinating enzyme in critical processes such as DNA damage repair, cell cycle regulation, and chromatin remodeling. Its proper activity requires nuclear localization via the nuclear localization signal (NLS) domain. When BAP1 undergoes a truncation mutation, the NLS loses its function and the protein is retained in the cytoplasm; whereas missense mutations in the UCH domain, whilst not necessarily altering subcellular localisation, can directly lead to the loss of deubiquitinase activity, thereby promoting tumour development.Consequently, elucidating the signaling pathways governed by BAP1, designing targeted therapeutic strategies for BAP1-mutant cancers, and implementing preventive interventions in BAP1 mutation carriers represent urgent clinical and research priorities.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary fatty acids intake and the risk of advanced cardiovascular-kidney-metabolic syndrome: evidence from NHANES 1999-2018.","authors":"Qiuhui Wang, Fengming Liang, Hongyang Xu, Yang Chen","doi":"10.1007/s10238-026-02251-y","DOIUrl":"10.1007/s10238-026-02251-y","url":null,"abstract":"<p><p>Cardiovascular-Kidney-Metabolic syndrome (CKM) is a multisystem disorder involving cardiovascular, renal, and metabolic dysfunction, with advanced stages (3-4) linked to high morbidity and mortality. Dietary fatty acids (FA) play critical roles in lipid metabolism, insulin sensitivity, and inflammation, yet their associations with CKM progression remain unclear. Data were from National Health and Nutrition Examination Survey, with stages 3-4 defined as advanced CKM. Dietary intake of total fat acids (TFA), saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) was derived from two 24-h recalls and energy-adjusted using the residual method. Multivariable logistic regression and restricted cubic splines assessed associations between FA and advanced CKM. Sensitivity and subgroup analyses were also performed. Among 27,166 participants (median age: 55.0 years; 52.2% male), 6,634 were classified in advanced CKM stages (3-4). Multivariable logistic regression showed that higher intakes of TFA, SFA, and MUFA were significantly associated with advanced CKM. Compared with the lowest quartile, adjusted odds ratios in the highest quartile were 1.35 (95% CI: 1.05-1.40), 1.26 (95% CI: 1.09-1.37), 1.30 (95% CI: 1.10-1.55), and 1.26 (95% CI: 1.09-1.47), respectively. Restricted cubic spline analyses supported positive linear associations across all four fatty acid categories. Findings remained robust in sensitivity analyses excluding cancer patients, and consistent across key subgroups, with no significant interactions observed. Higher dietary intakes of TFA, SFA, MUFA, and PUFA were associated with greater odds of advanced CKM stages. These findings suggest that dietary fat quantity and composition may be important correlates of CKM severity and warrant further investigation in prospective studies.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis-associated immune modulation enhances temozolomide efficacy in experimental glioblastoma: potential implications for T-cell infiltration and tumour microenvironment dynamics.","authors":"Shaik Rahaman, Roli Kushwaha, Divya Vohora, Sumana Chakravarty, Ahmed Kamal","doi":"10.1007/s10238-026-02243-y","DOIUrl":"10.1007/s10238-026-02243-y","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) remains a lethal and aggressive malignancy with limited response to standard therapies. This study hypothesized that artesunate, a ferroptosis inducer, enhances the cytotoxic and immunomodulatory efficacy of standard anticancer agents through mechanisms involving oxidative stress-mediated ferroptotic cell death and lipid peroxidation, influencing hypoxia-inducible factor-1α, insulin-like growth factor-1 (IGF-1), and leptin pathways. These pathways collectively regulate tumor proliferation, angiogenesis, and immune evasion; hence, their modulation may sensitize GBM to therapy. The study evaluated the therapeutic potential of artesunate in combination with anticancer drugs using in vitro GL261 glioblastoma cells and in vivo subcutaneous GL261 models. Clinically relevant agents representing distinct mechanisms, temozolomide, cyclophosphamide, paclitaxel, imatinib, and thymoquinone, were tested. Tumor volume, body weight, and serum biochemical parameters (IL-6, IGF-1, HIF-1α, and leptin) were analyzed, along with CD3 + T cell infiltration by immunohistochemistry. Combination treatments, particularly artesunate with temozolomide or paclitaxel, produced marked tumor regression compared with controls. Serum biomarker modulation and enhanced infiltration of CD3 + T cells indicated activation of ferroptotic and immune-mediated anti-tumor mechanisms, with minimal systemic toxicity. Artesunate potentiates the antitumor efficacy of standard chemotherapeutic agents through mechanisms involving ferroptosis and immune modulation, promoting a tumor-suppressive microenvironment. These findings support further mechanistic and translational studies toward developing ferroptosis-driven multimodal therapies for resistant glioblastomas.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the mechanism by which triphenyl phosphate promotes malignant phenotypes in bladder and kidney cancer through MMP9 based on bioinformatics analysis and experimental validation.","authors":"Hao Wang, Hongquan Liu, Qian Li, Fengze Sun, Jian Ma, Jitao Wu","doi":"10.1007/s10238-026-02159-7","DOIUrl":"10.1007/s10238-026-02159-7","url":null,"abstract":"<p><p>Background Bladder and kidney cancer burden rises globally, with environmental toxicants driving their progression. Methods We integrated global epidemiological analysis, single-cell transcriptomics, cell-cell communication analysis, epithelial subclustering, pseudotime inference, toxicological target prediction, survival modeling, cross-cohort validation, single-cell virtual knockout, spatial transcriptomic deconvolution, molecular docking/dynamics, CETSA, and in vitro assays to define a shared molecular interface linking triphenyl phosphate (TPP) to bladder and kidney cancer. Results Both malignancies exhibited age- and SDI-associated burden patterns. Single-cell profiling identified conserved epithelial, stromal, and immune ecosystems, with tumor epithelial cells occupying central positions in intercellular communication networks. Epithelial subclustering revealed a reproducible EMT-high subcluster 4 in both cancers, which localized to a terminal-like pseudotime state and was associated with poor survival. Predicted TPP targets intersected with subcluster 4 signatures and converged on extracellular matrix organization, adhesion, and leukocyte transendothelial migration pathways. Integrative survival modeling and multi-cohort validation identified MMP9 as a robust prognostic candidate associated with tumor progression. Importantly, single-cell virtual knockout of MMP9 revealed convergent remodeling of proliferative, inflammatory, hypoxia-related, and stress-response programs across bladder and renal cancer epithelial cells, highlighting conserved regulatory circuitry. Spatial transcriptomics further localized MMP9 to macrophage- and fibroblast-enriched niches in both tumor types. Structural modeling and CETSA supported an interaction between TPP and MMP9. Experimentally, TPP upregulated MMP9 at both mRNA and protein levels in T24 and 786-O cells; higher concentrations reduced viability, whereas lower concentrations enhanced migration and clonogenic growth. Conclusions TPP promotes the malignant phenotypes of bladder and kidney cancer via MMP9, which is validated by virtual knockout and in vitro experiments.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}