Experimental Hematology & Oncology最新文献

{"title":"Molecular mechanisms of viral oncogenesis in haematological malignancies: perspectives from metabolic reprogramming, epigenetic regulation and immune microenvironment remodeling.","authors":"Qing Xiao, Yi Liu, Xuejiao Shu, Ya Li, Xiaomei Zhang, Chaoyu Wang, Sanxiu He, Jun Li, Tingting Li, Tingting Liu, Yao Liu","doi":"10.1186/s40164-025-00655-2","DOIUrl":"https://doi.org/10.1186/s40164-025-00655-2","url":null,"abstract":"<p><p>Haematological malignancies are one of the most common tumors, with a rising incidence noted over recent decades. Viral infections play significant roles in the pathogenesis of these malignancies globally. This review delves into the contributions of various known viruses-specifically Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), human cytomegalovirus (HCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human papillomavirus (HPV)-in the development of haematological malignancies. These viruses are shown to drive tumorigenesis through mechanisms, such as metabolic reprogramming, epigenetic modifications, and remodeling of the immune microenvironment. By directly disrupting fundamental cellular functions and altering metabolic and epigenetic pathways, these viruses foster an immune milieu that supports both viral persistence and tumor growth. A thorough understanding of these viral oncogenic processes is crucial not only for etiological discovery but also for developing targeted interventions. This review emphasizes the need for continued research into the specific ways these viruses manipulate the host cell's metabolic and epigenetic environments, aiming to provide insights that could guide future advancements in treatment modalities.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"69"},"PeriodicalIF":9.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999317","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":"Cardiotoxicity of small-molecule kinase inhibitors in cancer therapy.","authors":"Shuangli Zhu, Kai Fu, Sijia Li, Chuan Yang, Can Pan, Xueping Wang, Fang Wang, Xiyong Yu, Kenneth Kin Wah To, Liwu Fu","doi":"10.1186/s40164-025-00660-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00660-5","url":null,"abstract":"<p><p>Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"68"},"PeriodicalIF":9.4,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005193","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":"Transcriptomic profiling of circulating tumor cells from metastatic breast cancer patients reveals new hints in their biological features and phenotypic heterogeneity.","authors":"Tania Rossi, Sara Bandini, Michele Zanoni, Michela Cortesi, Michela Palleschi, Erika Bandini, Andrea Rocca, Giulia Gallerani, Ivan Vannini, Meropi Plousiou, Lorenzo Gerratana, Antonino Musolino, Giovanni Tallini, Giovanni Martinelli, Ugo De Giorgi, Paola Ulivi","doi":"10.1186/s40164-025-00659-y","DOIUrl":"https://doi.org/10.1186/s40164-025-00659-y","url":null,"abstract":"<p><p>The study of circulating tumor cells (CTCs) provides critical insights into the biological mechanisms underlying metastasis. This study aims to demonstrate the applicability of an integrated DEPArray-based phenotypic analysis combined with transcriptomic characterization to investigate the biology of CTCs isolated from 10 patients with metastatic breast cancer (MBC). The transcriptional profiles of CTCs were consistent with both the cancer type and epithelial characteristics. Gene set enrichment analysis identified pathways associated with synapse organization and calcium channel activity. Furthermore, distinct gene expression profiles were linked to specific metastatic sites, particularly bone metastases. We also report a rare and understudied population of CTCs, characterized by the co-expression of epithelial and leukocyte markers, observed exclusively in patient-derived samples and not in blood samples from healthy volunteers spiked with SKBR-3 and MCF-7 cell lines. This suggests that these double-positive CTCs (dpCTCs) may have a specific role in the metastatic process. The transcriptomic characterization of these rare CTCs enhances our understanding of their biology and potential involvement in metastasis. As a pilot study, our findings underscore the potential of CTC-based transcriptomics as a valuable tool for advancing clinical and biological understanding of MBC, particularly regarding metastatic mechanisms and organotropism. Moreover, it provides preliminary insights into dpCTCs, a poorly characterized population that may play a pivotal role in metastasis but remains largely unexplored. These findings could pave the way for developing targeted therapies aimed at the pathways driving metastasis and for improving patient monitoring through CTC profiling.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"67"},"PeriodicalIF":9.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential.","authors":"Jing Tong, Yongci Tan, Wenwen Ouyang, Haocai Chang","doi":"10.1186/s40164-025-00636-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00636-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"65"},"PeriodicalIF":9.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964948","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":"IL-6-mediated tumorigenicity and antioxidant state in squamous cell carcinoma cells are driven by CD109 via stabilization of IL-6 receptor-alpha and activation of STAT3/NRF2 pathway.","authors":"Amani Hassan, Tenzin Kungyal, Shufeng Zhou, Meryem Blati, Kenneth Finnson, Nick Bertos, Nahid Golabi, Nader Sadeghi, Sampath Loganathan, Anie Philip","doi":"10.1186/s40164-025-00630-x","DOIUrl":"10.1186/s40164-025-00630-x","url":null,"abstract":"<p><strong>Background: </strong>Squamous cell carcinoma (SCC) is a prevalent malignancy and there are limited options to block the recurrence and metastasis that often occur in SCC patients. Although IL-6, a proinflammatory cytokine, is strongly implicated in SCC pathogenesis, its mechanism of action is poorly understood. The GPI-anchored membrane protein CD109 is frequently overexpressed in SCC and is associated with malignant transformation. The current study aims to investigate whether CD109 interacts with IL-6 receptor alpha (IL6Rα) and promotes IL-6-mediated oncogenic signaling to drive SCC progression.</p><p><strong>Methods: </strong>IL6Rα interaction with CD109 was determined by coimmunoprecipitation, immunohistochemistry, immunofluorescence and FACS analysis using human SCC (oral and vulvar) cell lines and human oral SCC tumors versus control tissue. Regulation of IL-6-induced signaling and antioxidant responses by CD109 was analyzed via STAT3/NRF2/SOD1/HO1 pathway activation. Regulation of IL-6-mediated tumorigenicity by CD109 was determined using stem cell marker expression and a spheroid formation assay. Clinical validation was achieved using genomic and proteomic analysis of oral SCC tumors and of head and neck SCC patient data.</p><p><strong>Results: </strong>We show that CD109 interacts with and stabilizes IL6Rα expression and promotes IL-6/STAT3/NRF2 pathway in oral and vulvar SCC cells. Loss of CD109 attenuates this pathway leading to loss of cancer cell stemness and decreased expression of superoxide dismutase1 and heme oxygenase-1, antioxidant proteins important for cell survival after chemotherapy. Furthermore, clinical validation of these findings was achieved through multi-omic analysis of oral SCC tumors and of head and neck SCC patient data.</p><p><strong>Conclusions: </strong>This work uncovers a previously unidentified mechanism in which CD109 serves as an essential regulator of IL6Rα expression and IL-6 mediated signaling in SCC cells, promoting stemness and antioxidant state, mechanisms known to mediate therapy resistance in SCC. Our findings establish a mechanistic validation for investigating the therapeutic utility of the CD109/ IL6Rα/STAT3/NRF2 pathway in SCC.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"64"},"PeriodicalIF":9.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990778","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":"Addressing graft-versus-host disease in allogeneic cell-based immunotherapy for cancer.","authors":"Zibai Lyu, Siyue Niu, Ying Fang, Yuning Chen, Yan-Ruide Li, Lili Yang","doi":"10.1186/s40164-025-00654-3","DOIUrl":"https://doi.org/10.1186/s40164-025-00654-3","url":null,"abstract":"<p><p>Allogeneic cell-based immunotherapies, particularly CAR-T cell therapy, represent a significant advancement in cancer treatment, offering scalable and consistent alternatives to autologous therapies. However, their widespread use is limited by the risk of graft-versus-host disease (GvHD). This review provides a comprehensive overview of GvHD in the context of allogeneic cell-based cancer immunotherapy and evaluates current strategies to mitigate its effects. Key strategies include genetic engineering approaches such as T cell receptor (TCR) knockout (KO) and T cell receptor alpha constant (TRAC) CAR knock-in. Alternative immune cell types like natural killer (NK) cells and natural killer T (NKT) cells offer potential solutions due to their lower alloreactivity. Additionally, stem cell technology, utilizing induced pluripotent stem cells (iPSCs), enables standardized and scalable production of engineered CAR-T cells. Clinical trials evaluating these strategies, such as UCART19 and CTX110, demonstrate promising results in preventing GvHD while maintaining anti-tumor efficacy. The review also addresses manufacturing considerations for allogeneic cell products and the challenges in translating preclinical findings into clinical success. By addressing these challenges, allogeneic cell-based immunotherapy continues to advance, paving the way for more accessible, scalable, and effective cancer treatments.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"66"},"PeriodicalIF":9.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971569","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":"Engineered nanoparticles for imaging and targeted drug delivery in hepatocellular carcinoma.","authors":"Xianzhe Yu, Qin Zhang, Leibo Wang, Yan Zhang, Lingling Zhu","doi":"10.1186/s40164-025-00658-z","DOIUrl":"https://doi.org/10.1186/s40164-025-00658-z","url":null,"abstract":"<p><p>Liver cancer, notably hepatocellular carcinoma (HCC), poses a significant global health burden due to its high fatality rates. Conventional antitumor medications face challenges, including poor targeting, high toxicity, and drug resistance, leading to suboptimal clinical outcomes. This review focused on nanoparticle use in diagnosing and delivering medication for HCC, aiming to advance the development of nanomedicines for improved treatment outcomes. As an emerging frontier science and technology, nanotechnology has shown great potential, especially in precision medicine and personalized treatment. The success of nanosystems is attributable to their smaller size, biocompatibility, selective tumor accumulation, and lower toxicity. Nanoparticles, as a central part of nanotechnology innovation, have emerged in the field of medical diagnostics and therapeutics to overcome the various limitations of conventional chemotherapy, thus offering promising applications for improved selectivity, earlier and more precise diagnosis of cancers, personalized treatment, and overcoming drug resistance. Nanoparticles play a crucial role in drug delivery and imaging of HCC, with the body acting as a delivery system to target and deliver drugs or diagnostic reagents to specific organs or tissues, helping to accurately diagnose and target therapies while minimizing damage to healthy tissues. They protect drugs from early degradation and increase their biological half-life.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"62"},"PeriodicalIF":9.4,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975450","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":"Hypomagnesemia in lymphoma patients receiving CAR T therapy correlates with immune dysfunction and decreased survival.","authors":"Jennifer J Gile, Patrizia Mondello, Zixing Wang, Ying Li, Radhika Bansal, Sangeetha Gandhi, Henan Zhang, Elham Babadi, Kodi Martinez, Gabrielle McCoy, Zuoyi Shao, Kevin Regan, Matthew A Hathcock, Panwen Wang, Junwen Wang, Abdullah S Al Saleh, Gordon Ruan, Stephen M Ansell, N Nora Bennani, Patrick B Johnston, Jonas Paludo, Jose C Villasboas-Bisneto, Arushi Khurana, Urshila Durani, Yucai Wang, Paul J Hampel, Allison Rosenthal, Javier Munoz, Eider Moreno, Januario E Castro, Hemant S Murthy, Mohamed Kharfan-Dabaja, Saad S Kenderian, Jenny J Kim, Rhine Shen, Mike Mattie, Yi Lin, Thomas E Witzig","doi":"10.1186/s40164-025-00623-w","DOIUrl":"https://doi.org/10.1186/s40164-025-00623-w","url":null,"abstract":"<p><strong>Background: </strong>Hypomagnesemia has been correlated with inferior outcomes in patients with large B cell lymphoma (LBCL) undergoing stem cell transplants. As T-cell and myeloid cell dysfunction have been associated with low magnesium conditions, we investigated whether serum magnesium (Mg) levels could predict clinical outcomes in LBCL patients who received chimeric antigen receptor T-cell therapy.</p><p><strong>Methods: </strong>Patients with LBCL who received axi-cel under the ZUMA-1 trial or as FDA approved therapy at Mayo Clinic were examined. Serum samples were obtained at specified time points and cytokine analysis was performed. Single cell RNA sequencing was performed on peripheral blood mononuclear cells. The Student T-test, Kruskal Wallis, or Fisher's Exact Tests were used to compare differences in demographics across Mg levels. Survival curves were plotted using the Kaplan-Meier methodology and compared using the Wilcoxon test.</p><p><strong>Results: </strong>We found that hypomagnesemia before lymphodepletion chemotherapy predicted inferior progression-free and overall survival in the pivotal study ZUMA-1 (NCT02348216). These results were validated in an independent cohort of LBCL patients receiving axicabtagene ciloleucel (axi-cel) at Mayo Clinic. Hypomagnesemia correlated with increased inflammatory serum markers and cytokine levels including ferritin, IL-6, IL1Ra, IL-8, and MIP1a. scRNAseq analysis unveiled altered immune interactions between monocytes and T cells with a concordant immune suppressive transcriptome.</p><p><strong>Conclusions: </strong>Hypomagnesemia at the time of CAR-T infusion is associated with an unfavorable inflammatory profile and decreased response and survival in LBCL patients receiving axi-cel. These findings suggest a potentially actionable prognostic factor for patients with large cell lymphoma undergoing CAR-T.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"63"},"PeriodicalIF":9.4,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994513","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":"Hypomethylating agents plus venetoclax for high-risk MDS and CMML as bridge therapy to transplant: a GESMD study.","authors":"Ines Zugasti, Monica Lopez-Guerra, Sandra Castaño-Díez, Daniel Esteban, Alejandro Avendaño, Helena Pomares, Ana Perez, Sara García-Ávila, Irene Padilla Conejo, Cristina de la Fuente Montes, Alexandra Martínez-Roca, Beatriz Merchán, Carlos Jiménez-Vicente, Francesca Guijarro, Jose Ramón Álamo, Albert Cortes-Bullich, Victor Torrecillas, Lucia Mont, Esther Carcelero, Gisela Riu, Lurdes Zamora, Joan Bargay, Ana Triguero, Maria Suarez-Lledó, Maria Queralt Salas, Felix López-Cadenas, Fernando Ramos, Blanca Xicoy, David Valcárcel, Montserrat Arnan, Carmen Martínez, Montserrat Rovira, Francesc Fernández-Avilés, Maria Díez-Campelo, Jordi Esteve, Marina Díaz-Beyá","doi":"10.1186/s40164-025-00652-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00652-5","url":null,"abstract":"<p><strong>Background: </strong>High-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) remain therapeutic challenges with suboptimal outcomes. The only potentially curative treatment is allogeneic stem cell transplantation (allo-SCT). The most frequent pre-allo-SCT treatment is monotherapy with hypomethylating agents (HMA), but approximately 40% of patients cannot proceed to allo-SCT, mainly due to disease progression. Recent evidence suggests that combining HMA with venetoclax (HMA/VEN) could increase HMA efficacy in HR-MDS but it remains unclear if this combination could bridge more patients to allo-SCT.</p><p><strong>Methods: </strong>We retrospectively evaluated HMA/VEN as a bridge to allo-SCT in 30 patients with HR-MDS or CMML eligible for transplant. Eighteen patients were treatment-naïve and 12 were refractory or relapsed (R/R).</p><p><strong>Results: </strong>As defined by the IWG 2023 criteria, the overall response rate (ORR) was 90% and the composite complete response rate was 77%. For the R/R patients, ORR was 83%. The allo-SCT rate was 83%, and the allo-SCT rate of those patients treated exclusively with HMA/VEN without further bridge therapies was 76%. One- and two-year post-allo-SCT survival was 75% and two-year cumulative incidence of relapse was 30.5%. Follow-up of measurable residual disease identified some molecular relapses that were controlled with preemptive treatment.</p><p><strong>Conclusions: </strong>Our findings indicate that HMA/VEN combination therapy shows promise as a bridging strategy to allo-SCT in HR-MDS and CMML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"61"},"PeriodicalIF":9.4,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963794","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":"Sarcosine sensitizes lung adenocarcinoma to chemotherapy by dual activation of ferroptosis via PDK4/PDHA1 signaling and NMDAR-mediated iron export.","authors":"Guangyao Shan, Yunyi Bian, Shencheng Ren, Zhengyang Hu, Binyang Pan, Dejun Zeng, Zhaolin Zheng, Hong Fan, Guoshu Bi, Guangyu Yao, Cheng Zhan","doi":"10.1186/s40164-025-00657-0","DOIUrl":"https://doi.org/10.1186/s40164-025-00657-0","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms.</p><p><strong>Methods: </strong>An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine's effects on ferroptosis. Metabolic fate was studied using ¹⁵N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues.</p><p><strong>Results: </strong>Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models.</p><p><strong>Conclusion: </strong>Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"60"},"PeriodicalIF":9.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992912","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}