Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Tumor cells promote immunosuppression in ovarian cancer via a positive feedback loop with MDSCs through the SAA1-IL-1β axis.","authors":"Haoran Hu, Meiqin Yang, Baoyou Huang, Jianyi Ding, Yashi Zhu, Xinxin Xu, Bo Yin, Huijuan Zhou, Tiefeng Huang, Mengjie Li, Yifan Kou, Zilale Rahim, Ang Li, Wei Wang, Lingfei Han","doi":"10.1186/s13046-025-03536-y","DOIUrl":"https://doi.org/10.1186/s13046-025-03536-y","url":null,"abstract":"<p><strong>Background: </strong>Immune tolerance in epithelial ovarian cancer (EOC) enables cancer cells to evade immune surveillance. Myeloid-derived suppressor cells (MDSCs), as crucial immunosuppressive regulators, shape the tumor microenvironment and contribute to resistance against immunotherapy. However, the regulatory mechanisms of MDSCs in ovarian cancer remain poorly understood.</p><p><strong>Methods: </strong>We examined the presence and distribution of MDSCs in peripheral blood and tumor tissues from EOC patients. Transcriptomic analysis was performed on ovarian cancer cells co-cultured with MDSCs. The role of Serum Amyloid A1 (SAA1) was investigated through in vitro functional assays, co-culture experiments, and in vivo mouse models.</p><p><strong>Results: </strong>MDSCs were enriched in both peripheral blood and tumor tissues of EOC patients. SAA1 was significantly upregulated in ovarian cancer cells after interaction with MDSCs and confirmed in tumor samples and cell lines. Functionally, SAA1 promoted cancer cell proliferation, migration, and invasion. It also recruited MDSCs via TLR2/4, induced the differentiation of granulocyte-monocyte progenitors (GMPs), and stimulated IL-1β secretion, which in turn enhanced SAA1 expression, forming a positive feedback loop. In vivo, SAA1 promoted tumor progression and ascites formation. Clinically, high levels of SAA1, IL-1β, and CD33⁺ MDSCs correlated with poor survival.</p><p><strong>Conclusion: </strong>This study uncovers a novel SAA1-IL-1β feedback loop that promotes immunosuppression and progression in ovarian cancer. These findings provide insight into tumor-immune interactions and suggest a potential biomarker and therapeutic target for EOC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"277"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201976","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":"Mechanistic models position ceritinib as a nuclear integrity disrupting therapy in pediatric liver tumors.","authors":"Salih Demir, Thomas Kessler, Alina Hotes, Beate Häberle, Eiso Hiyama, Tomoro Hishiki, Emilie Indersie, Sophie Branchereau, Christian Vokuhl, Mathurin Dorel, Hans Lehrach, Bodo Lange, Stefano Cairo, Roland Kappler","doi":"10.1186/s13046-025-03535-z","DOIUrl":"10.1186/s13046-025-03535-z","url":null,"abstract":"<p><strong>Background: </strong>Pediatric liver tumors with high-risk features pose therapeutic challenges, necessitating the development of more targeted and effective treatment strategies. Computational modeling of virtual patients and in silico drug response simulations, based on properly trained mechanistic models, is a powerful strategy to predict new treatment options. We aimed to leverage patient-specific mechanistic cell models to identify therapeutic alternatives for pediatric patients with high-risk liver tumors.</p><p><strong>Methods: </strong>We generated digital twins of high-risk pediatric liver tumor patients by integrating clinical, genetic, and transcriptomic data and performed computational drug response simulations using mechanistic models. We validated the therapeutic potential of ceritinib in patient-derived xenograft models both in vitro and in vivo and used fluorescence microscopy-based imaging for functional analyses.</p><p><strong>Results: </strong>Mechanistic models trained with digital twins of high-risk pediatric liver tumor patients identified ceritinib as the most effective treatment option through iterated in silico drug response simulations. Validation on a comprehensive drug-testing platform demonstrated that ceritinib, unlike other ALK receptor tyrosine kinase inhibitors with lower prediction scores, inhibited tumor growth by targeting non-canonical kinases. Mechanistically, ceritinib suppressed expression of nucleoporins, essential components of the nuclear pore complex overexpressed in pediatric liver tumors, consequently leading to the disruption of nuclear membrane integrity, perinuclear accumulation of mitochondria, production of reactive oxygen species, and induction of apoptosis. In patient-derived xenograft mouse models, ceritinib reduced tumor burden and extended survival by promoting cell death.</p><p><strong>Conclusion: </strong>This study demonstrates the successful application of mechanistic models on virtual patients to position ceritinib as a promising therapeutic agent for high-risk pediatric liver tumors, highlighting its impact on key kinases implicated in tumor aggressiveness and its ability to compromise nuclear integrity.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"268"},"PeriodicalIF":12.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088070","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":"Correction: HMGA1-TRIP13 axis promotes stemness and epithelial mesenchymal transition of perihilar cholangiocarcinoma in a positive feedback loop dependent on c-Myc.","authors":"Zhipeng Li, Jialiang Liu, Tianli Chen, Rongqi Sun, Zengli Liu, Bo Qiu, Yunfei Xu, Zongli Zhang","doi":"10.1186/s13046-025-03526-0","DOIUrl":"10.1186/s13046-025-03526-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"267"},"PeriodicalIF":12.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071117","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":"Correction: Elucidating the role of N‑myristoylation in the excessive membrane localization of PD‑L1 in hypoxic cancers and developing a novel NMT1 inhibitor for combination with immune checkpoint blockade therapy.","authors":"Haoming Zhao, Zhen Zhang, Chaojun Zhang, Hexin Ma, Qingqing Wan, Xinran Zhao, Xu Wang, Ming Yan, Haiyan Guo, Jianjun Zhang, Wantao Chen","doi":"10.1186/s13046-025-03533-1","DOIUrl":"10.1186/s13046-025-03533-1","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"266"},"PeriodicalIF":12.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994216","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":"Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder cancer.","authors":"Tinghao Li, Kunyao Zhu, Hang Tong, Yan Sun, Junlong Zhu, Zijia Qin, Junrui Chen, Linfeng Wu, Xiaoyu Zhang, Aimin Wang, Xin Gou, Hubin Yin, Weiyang He","doi":"10.1186/s13046-025-03487-4","DOIUrl":"10.1186/s13046-025-03487-4","url":null,"abstract":"<p><strong>Background: </strong>A significant challenge in bladder cancer treatment is primary chemoresistance, in which cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a pivotal role. While the contributions of CAFs to tumor progression and drug resistance are well established, the precise molecular mechanisms by which they induce chemoresistance remain unclear. A comprehensive understanding of the effect of TME modulation-particularly through CAFs-on the chemotherapeutic response is crucial for developing effective strategies to overcome chemoresistance and improve patient survival.</p><p><strong>Methods: </strong>Primary fibroblasts were isolated from paired clinical samples of bladder cancer tissues and adjacent normal tissues to identify key CAF-derived secretory factors. Bioinformatics analysis, semiquantitative RT‒qPCR, and dual-luciferase reporter assays were subsequently used to investigate the functional role and mechanistic basis of CXCL14 in chemoresistance. The therapeutic relevance of these findings was further evaluated through in vitro and in vivo models, including ex vivo patient-derived organoid (PDO) models, by assessing cisplatin sensitivity and validating therapeutic targeting of the CXCL14-CCR7-STAT3 axis with small molecule inhibitors.</p><p><strong>Results: </strong>Compared to normal fibroblasts and CAFs from nonchemoresistance groups, CAFs derived from cisplatin-resistant patients demonstrated significantly greater paracrine-mediated induction of chemoresistance. Mechanistically, CAF-secreted CXCL14 engaged CCR7 on bladder cancer cells, triggering STAT3 phosphorylation and consequently upregulating the DNA repair gene ERCC4 to promote cisplatin resistance. In vivo validation confirmed that pharmacological CCR7 or STAT3 inhibition markedly reversed chemoresistance and potentiated cisplatin-induced tumor cell death. Notably, STAT3 activation mediated the overexpression of the glycolytic enzymes HK2 and LDHA, resulting in greater glycolytic flux in resistant cells. This metabolic reprogramming further facilitated the transdifferentiation of normal fibroblasts into CXCL14-secreting CAFs, establishing a self-reinforcing feedback loop that sustains chemoresistance.</p><p><strong>Conclusion: </strong>The CXCL14/CCR7/STAT3 axis critically mediates cisplatin resistance in bladder cancer through dual modulation of DNA repair and glycolytic metabolism. Therapeutic cotargeting of this pathway with CCR7 or STAT3 inhibitors combined with cisplatin represents a promising strategy to overcome chemoresistance and improve clinical outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"265"},"PeriodicalIF":12.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977164","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":"ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs.","authors":"Giovanna Talarico, Mara Lecchi, Anna Zanichelli, Paola Portararo, Laura Botti, Vera Cappelletti, Massimo Costanza, Annamaria Piva, Pietro Pratesi, Francesco Bertolini, Massimo Di Nicola, Claudio Tripodo, Valeria Cancila, Serenella Maria Pupa, Mario Paolo Colombo, Claudia Chiodoni, Paolo Verderio, Sabina Sangaletti","doi":"10.1186/s13046-025-03518-0","DOIUrl":"10.1186/s13046-025-03518-0","url":null,"abstract":"<p><strong>Background: </strong>High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs).</p><p><strong>Methods: </strong>In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature.</p><p><strong>Results: </strong>We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells.</p><p><strong>Conclusion: </strong>These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"264"},"PeriodicalIF":12.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977243","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":"Crosstalk between heterogeneous cancer-associated fibroblast subpopulations and the immune system in breast cancer: key players and promising therapeutic targets.","authors":"Lu Liu, Weijun Wan, Yilin Chang, Luoquan Ao, Yan Xu, Xiang Xu","doi":"10.1186/s13046-025-03527-z","DOIUrl":"10.1186/s13046-025-03527-z","url":null,"abstract":"<p><p>The tumor microenvironment (TME) of breast cancer is a complex ecosystem, in which cancer-associated fibroblasts (CAFs), as the most abundant stromal cell type, meticulously construct an ecological niche that supports tumor growth through mechanisms including extracellular matrix (ECM) remodeling, secretion of bioactive factors, and interactions with neighboring cells. High-resolution technologies, including single-cell sequencing and spatial transcriptomics, have revealed the high heterogeneity, functional diversity, and spatial distribution within the CAF population. Significant differences exist in the interactions between distinct CAF subpopulations and immune cells. Through complex crosstalk with the immune system, they collaboratively establish an immunosuppressive network, becoming a core driving force for tumor immune escape. This review focuses on the latest research advances in heterogeneous subpopulations of CAFs within the breast cancer microenvironment, delves into how the complex bidirectional crosstalk between different CAF subpopulations and immune cells collaboratively shapes the tumor immune microenvironment (TIME), and summarizes various CAF-based therapeutic strategies for breast cancer, aiming to provide critical theoretical basis and novel therapeutic perspectives for the clinical translation of CAF heterogeneity research.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"263"},"PeriodicalIF":12.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977221","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":"E2F1-autophagy-ALDH1A1 axis enhances self-renewal and drug resistance of lung cancer stem-like cells in a p53-dependent manner.","authors":"Jingyuan Li, Yiyu Chen, Jianyu Wang, Liyuan Liu, Javeria Qadir, Dan Xie, Xue Wan, Yanan Luo, Jiawen Xian, Ting Ye","doi":"10.1186/s13046-025-03506-4","DOIUrl":"https://doi.org/10.1186/s13046-025-03506-4","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD) is a predominant subtype of non-small cell lung adenocarcinoma (NSCLC). It is typically asymptomatic and associated with high mortality rates. Despite recent advancements in screening technologies and therapeutic approaches, its pathogenesis still remains elusive. Therefore, it is imperative to explore new diagnostic markers and therapeutic targets for LUAD management. Cancer stem cells (CSCs) have high self-renewal capacity and incur therapeutic resistance, thus, considered as crucial elements in initiating and promoting tumor development. Contextual to this, the present study reveals the role of the transcriptional activator E2F1 in LUAD oncogenesis and its association with various biological characteristics of lung cancer stem cells (LCSCs). Whereby, it may also serve as a crucial factor in regulating autophagy. Autophagy can modulate stemness by either promoting or inhibiting CSCs characteristics. Pertinently, our study integrated bioinformatics, in-vitro and in-vivo experiments to elucidate that E2F1 can induce ALDH1A1 through autophagy, thus promoting self-renewal and drug resistance of LCSCs, as well as tumorigenicity. Mechanistically, \"E2F1-autophagy-ALDH1A1\" axis enhanced the self-renewal capacity and drug resistance of LCSCs in a p53-dependent manner, highlighting the potential of E2F1 as a promising marker for LUAD.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"261"},"PeriodicalIF":12.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977177","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":"Investigating the role of UBASH3B in cancer: structural relevance, physiological functions, and therapeutic possibilities.","authors":"Sophie Werner, Cameron Westlake, Madeleine Ndahayo, Ishita Gupta, Daria A Gaykalova","doi":"10.1186/s13046-025-03511-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03511-7","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally and presents a persistent clinical challenge due to the limited availability of effective targeted therapeutics. Recent studies have identified the ubiquitin-associated and SH3 domain-containing B (UBASH3B), a tyrosine phosphatase, as a key oncogenic player in HNSCC pathogenesis. Elevated UBASH3B expression correlates with poor clinical outcomes in HNSCC patients. Mechanistically, UBASH3B promotes tumor progression by stabilizing the epidermal growth factor receptor (EGFR) levels, thereby enhancing downstream signaling pathways that promote cancer cell proliferation, survival, and therapeutic resistance. In this review, we provide a comprehensive overview of the structural features and physiological functions of UBASH3B, along with a focused discussion on its emerging role in HNSCC tumorigenesis. We further explore the potential of targeting UBASH3B as a novel therapeutic target, underscoring its promise in reshaping treatment paradigms. Elucidating the molecular functions of UBASH3B in HNSCC may uncover new vulnerabilities and pave the way for the development of novel therapeutic strategies that target its activity.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"262"},"PeriodicalIF":12.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977296","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":"Bufalin inhibits hepatocellular carcinoma progression by blocking EGFR-mediated RAS-RAF-MEK-ERK pathway activation.","authors":"Jingwen Liu, Jia Jiang, Ju Huang, Zhi-E Fang, Lexi Liu, Yong Liu, Weiqi Nian, Jianyuan Tang, Zhilei Wang","doi":"10.1186/s13046-025-03531-3","DOIUrl":"10.1186/s13046-025-03531-3","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies with persistently dismal long-term survival outcomes despite multidisciplinary advances in diagnostic and therapeutic strategies. Cinobufacini preparations have garnered increasing attention as adjunctive therapeutic agents in integrated management strategies for HCC. Bufalin (BF), the active ingredient in Cinobufacini, has garnered substantial attention due to its potent antitumor effects. However, the precise molecular mechanisms underlying its antitumor actions remain incompletely characterized.</p><p><strong>Methods: </strong>A clinical retrospective cohort analysis was conducted to establish the definitive clinical benefit of Cinobufacini in improving treatment outcomes among HCC patients. Building upon these clinical insights, a multi-dimensional approach was implemented to elucidate the anti-HCC molecular mechanisms mediated by the bioactive component BF of Cinobufacini.</p><p><strong>Results: </strong>Western medical treatment combined with Cinobufacini shows an improving trend in the overall survival (OS) and progression free survival (PFS) of HCC patients. Moreover, our exploratory analysis suggests a potential dose-response relationship where longer cumulative exposure to Cinobufacini appears to be associated with improved clinical outcomes. In vitro experiments demonstrated that BF significantly inhibited cell viability and proliferation, and induced apoptosis in HepG2 and HCCLM3. Network pharmacology analysis identified 20 core targets, and molecular docking revealed high-affinity binding between BF and key proteins, including EGFR, GRB2, SRC, and MAPK1. HCC tissue microarrays confirmed the overexpression of EGFR and GRB2 in HCC tissues. Further mechanistic investigations revealed that BF suppressed the EGFR-mediated RAS/RAF/MEK/ERK pathway activation in HepG2 and HCCLM3. BF intervention significantly reduced tumor volumes in C57BL/6 mouse subcutaneous HCC xenograft and BALB/c Nude mouse orthotopic HCC xenograft models. Moreover, BF inhibited the phosphorylation levels of EGFR, RAF, MEK, and ERK in tumor tissues, further corroborating its inhibitory effects on the RAS/RAF/MEK/ERK signaling pathway.</p><p><strong>Conclusions: </strong>Our observational data suggest a potential association between Cinobufacini use and favorable trends in OS and PFS among HCC patients. BF exerts its antitumor effects against HCC by interfering with the EGFR-mediated RAS/RAF/MEK/ERK signaling pathway. These findings not only elucidate the molecular mechanisms underlying the antitumor actions of BF but also highlight the potential of Cinobufacini preparations as a valuable therapeutic option for HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"260"},"PeriodicalIF":12.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977066","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}