Oncogene最新文献

{"title":"FOXA2 sensitizes endometrial carcinoma to progestin-mediated conservative therapy by triggering PR transcriptional activation.","authors":"Jie Liu, Jingyuan Ning, Yiqin Wang, Xiangjun He, Donglai Wang, Jingyi Zhou, Jianliu Wang","doi":"10.1038/s41388-025-03564-0","DOIUrl":"https://doi.org/10.1038/s41388-025-03564-0","url":null,"abstract":"<p><p>Progesterone receptor (PR) expression correlates strongly with progestin sensitivity in fertility-sparing therapy for endometrial carcinoma (EC). However, the mechanisms governing PR expression remain incompletely defined. Here, by stratifying EC patients into PR-high and PR-low groups, we observe that PR-low tumors exhibit enhanced invasion and metastasis signatures, whereas PR-high tumors display increased fatty acid metabolism. Through integrated network analysis, transcriptional correlation across multiple cohorts, and single-cell transcriptomic profiling, FOXA2 is identified as a master regulator of PR expression. Specifically, FOXA2 directly binds the PR promoter, which, in turn, transcriptionally activates PR expression and increases the sensitivity of EC cells to medroxyprogesterone acetate (MPA), an oral progestin used in clinical. Overexpression of FOXA2 markedly inhibits tumor progression, evidenced with reduced cell proliferation and migration while elevated apoptosis. Moreover, FOXA2 is critically involved in lipid metabolic modulation and the administration of Orlistat, an FDA-approval inhibitor of fatty acid synthase, elevates FOXA2 and PR expression, subsequently enhancing progestin sensitivity both in vitro and in vivo. Collectively, our findings identify FOXA2 as a key regulator in controlling PR levels in EC cells and propose the activation of FOXA2-PR axis via Orlistat treatment as a promising therapeutic strategy to improve progestin responsiveness in EC patients.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058586","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":"FK228 reshapes tumor microenvironment to enhance anti-PD-L1 efficacy","authors":"Liang Gong,&nbsp;Lu Tian,&nbsp;He Li,&nbsp;Kexuan Zhou,&nbsp;Haocheng He,&nbsp;Shuai Xiao,&nbsp;Yizhun Zhu,&nbsp;Zhicheng Gong,&nbsp;Kaisa Cui,&nbsp;Youming Zhang","doi":"10.1038/s41388-025-03558-y","DOIUrl":"10.1038/s41388-025-03558-y","url":null,"abstract":"The lack of a favorable tumor immune microenvironment (TIME) results in limited response rates to immune checkpoint blockade (ICB) across human solid tumors, necessitating the development of novel combination strategies. In this study, we repurposed FK228, an US FDA-approved histone deacetylase inhibitor that is used clinically in non-solid tumor treatment, as a novel ICB sensitizer in solid tumors and revealed the diverse regulatory functions of FK228 in the TIME. FK228 serves as a novel necroptosis inducer in cancer cells by triggering endoplasmic reticulum stress. This in turn enhances the immunogenicity of cancer cells and increases the infiltration of tumor-killing immunocytes, including CD8+ T and natural killer cells, particularly activating tumor-infiltrated CD8+ T cells. Meanwhile, FK228 treatment shifts macrophages toward the pro-inflammatory phenotype. Moreover, the combined use of FK228 and a PD-L1 inhibitor significantly delay tumor growth and extend the survival of tumor bearing mice. Overall, our findings reveal new possibilities for the clinical application of FK228 in solid tumors and underscore the critical role of histone deacetylases in maintaining the immune-unfavorable TIME.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3665-3678"},"PeriodicalIF":7.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03558-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054837","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":"EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from endoplasmic reticulum associated degradation to impair ferroptosis susceptibility","authors":"Xinrui Dong,&nbsp;Huijuan Dai,&nbsp;Linli Yao,&nbsp;Yanping Lin,&nbsp;Yaohui Wang,&nbsp;Ye Li,&nbsp;Xueli Zhang,&nbsp;Liheng Zhou,&nbsp;Jinsong Lu,&nbsp;Wenjin Yin","doi":"10.1038/s41388-025-03545-3","DOIUrl":"10.1038/s41388-025-03545-3","url":null,"abstract":"Cholesterol biosynthesis is more activated in triple negative breast cancer (TNBC) than in other subtype breast cancer and plays essential role in facilitating TNBC. However, the regulatory network and how cholesterol biosynthesis contribute to TNBC development and progression are not well elucidated. Here, we found that reticulum membrane protein complex 2 (EMC2) is highly expressed in TNBC and predicts short survival of patients. In vitro and in vivo experiments displayed that EMC2 could promote TNBC growth. We also displayed that EMC2 could increase intracellular cholesterol biosynthesis by regulating Farnesyltransferase 1 (FDFT1) expression. Mechanistically, we validated that EMC2 interacted with heat shock protein 90(HSP90) to sustain FDFT1 protein quality and correctly located in the ER membrane through protecting it from endoplasmic reticulum associated degradation (ERAD). Furthermore, EMC2 decreased TNBC cell ferroptosis susceptibility through elevating intracellular cholesterol contents. Collectively, our findings shed a new insight that EMC2 is critical for boosting cholesterol biosynthesis and ferroptosis resistance. Targeting EMC2 could be a promising novel therapeutic target for TNBC treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3713-3728"},"PeriodicalIF":7.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03545-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033827","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":"LEF1 confers resistance to DNA-damaging chemotherapies through upregulation of PARP1 and NUMA1 in ovarian cancer.","authors":"Lin Huang, Mengna Zhu, Mengqing Chen, Feiquan Ying, Qiulei Wu, Pan Liu, Wenhan Li, Guoqing Li, Yuewen Gao, Shuyan Yi, Wenwen Wang, Yiping Wen, Si Sun, Jing Cai, Man Xiao","doi":"10.1038/s41388-025-03561-3","DOIUrl":"https://doi.org/10.1038/s41388-025-03561-3","url":null,"abstract":"<p><p>Resistance to platinum-based drugs and PARP inhibitors (PARPi) is the leading cause of treatment failure in epithelial ovarian cancer (EOC). This study aimed to identify resistance mechanisms shared by both. Using bioinformatic analyses, EOC tissues, primary tumor cells and organoids, and chemoresistant cell lines, we identified lymphoid enhancer-binding factor 1 (LEF1) as a candidate, whose expression was increased in both platinum-resistant and PARPi-resistant tumors. Moreover, LEF1 deficiency increased EOC cell sensitivity to cisplatin and PARPi in vitro and in vivo. Mechanistically, LEF1 knockdown promoted double-strand breaks and significantly impaired both homologous recombination and nonhomologous end joining by directly downregulating the transcription of PARP1 and NUMA1. In addition, the LEF1 inhibitor niclosamide increased ovarian cancer sensitivity to Cisplatin and PARPi in patient-derived organoids and Niraparib-resistant cell lines. These findings indicate that LEF1 is a potential therapeutic target for overcoming resistance to chemotherapy based on platinum and PARPi in EOC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033897","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":"A novel FAP-targeting antibody-exatecan conjugate improves immune checkpoint blockade by reversing immunosuppressive microenvironment in pancreatic cancer.","authors":"Xiaobao Wei, Jiangchao Wu, Wanyue Cao, Qitai Chen, Zhenduo Shao, Chengyang Hu, Yize Zhang, Weining Weng, Tao Meng, Xun Meng, Tingbo Liang, Qi Zhang","doi":"10.1038/s41388-025-03567-x","DOIUrl":"https://doi.org/10.1038/s41388-025-03567-x","url":null,"abstract":"<p><p>Pancreatic cancer is a highly aggressive malignancy with a dismal prognosis, characterized by a complex tumor microenvironment that promotes immunosuppression and limits the efficacy of immune checkpoint blockade (ICB) therapy. Fibroblast activation protein (FAP) is overexpressed in the tumor stroma and represents a promising target for therapeutic intervention. Here, we developed a novel antibody-drug conjugate (ADC) targeting FAP, and investigated its anti-tumor activity and ability to enhance ICB efficacy in pancreatic cancer. We conjugated a humanized anti-FAP antibody with the potent topoisomerase I inhibitor exatecan to generate a novel FAP-targeting ADC (FAP-ADC) with a drug-to-antibody ratio of eight. The cytotoxicity and internalization of FAP-ADC were evaluated in vitro using FAP-expressing cell lines, and its anti-tumor activity was assessed in vivo using cell-derived xenograft models. Mechanistic studies revealed that FAP-ADC synergistically improved the efficacy of anti-PD-L1 antibody in vivo by leading to an increased level of M1-polarized macrophages and reduced abundance of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Furthermore, FAP-ADC treatment enhanced the infiltration of CD8⁺ T cells into the tumor and upregulated the expression of pro-inflammatory cytokines. Combination therapy with FAP-ADC and anti-PD-L1 antibodies resulted in superior anti-tumor efficacy compared to either monotherapy. Collectively, our novel FAP-targeting ADC exerts potent anti-tumor activity in pancreatic cancer by selectively depleting FAP-expressing cells and reversing the immunosuppressive tumor microenvironment. The combination of FAP-ADC with ICB therapy represents a promising therapeutic strategy to improve the treatment outcomes for patients with this fatal cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033852","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":"Correction: Liquid-liquid phase separation of GPS2-LATS1 promotes colorectal cancer progression by reprogramming lipid metabolism","authors":"Yuliang Ren,&nbsp;Junjie Chen,&nbsp;Xiangrong Zhan,&nbsp;Songran Sheng,&nbsp;Yifan Zhong,&nbsp;Manxiang Gu,&nbsp;Xuewen Liu,&nbsp;Liang Zhang,&nbsp;Lei Bao,&nbsp;Yuan Si,&nbsp;Ying Liu","doi":"10.1038/s41388-025-03540-8","DOIUrl":"10.1038/s41388-025-03540-8","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3755-3758"},"PeriodicalIF":7.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03540-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033825","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":"Extracellular vesicles of cancer cells induce FOXP3+ fibroblasts and facilitate tumor invasion via the Wnt3-β-catenin pathway.","authors":"Tomoaki Kimura, Kurara Takagane, Go Itoh, Sei Kuriyama, Kenji Meguro, Souichi Koyota, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Shuichi Tsukamoto, Naozane Nomura, Masafumi Horie, Motonobu Saito, Akiteru Goto, Masakazu Yashiro, Junichi Arita, Masamitsu Tanaka","doi":"10.1038/s41388-025-03552-4","DOIUrl":"https://doi.org/10.1038/s41388-025-03552-4","url":null,"abstract":"<p><p>Forkhead-box-protein P3 (FOXP3) is a key transcription factor in T regulatory cells (Tregs). However, its expression and significance in non-immune stromal cells in the tumor microenvironment remain unclear. Here, we demonstrated FOXP3 expression in stromal fibroblasts of mouse and human gastrointestinal tumors. Immunohistological examination revealed FOXP3 expression in αSMA⁺ collagen I⁺ myofibroblasts. In the mouse omentum inoculated with gastric cancer cells, cytokeratin^(-)/CD45^(-)/FoxP3⁽⁺⁾ stromal cells were identified via flow-cytometry, and high FOXP3 expression was noted in fibroblasts surrounding the tumor glands, where CD8⁺ T cells were exclusively infiltrated. Extracellular vesicles (EVs) from mouse gastric cancer cells upregulated Foxp3 transcription in fibroblasts, which partly depends on increase of transcription factors including NFAT1 and c-Rel, and activation of TGF-β and STAT5 pathways. In FOXP3⁽⁺⁾ fibroblasts, immunosuppressive cytokines including IL-10 and CCL2 were upregulated. FOXP3 overexpression in NIH/3T3 fibroblasts enhanced Wnt3a-induced β-catenin responses, accompanied by cell growth and tumor invasion in mice stomach. As the mechanism, FOXP3 induced CDH11 expression in fibroblasts, which augmented the Wnt3/β-catenin pathway, and blocking of CDH11 suppressed tumor invasion mediated by FOXP3⁽⁺⁾ fibroblasts. Our results suggest that cancer cell-derived EVs regulate FOXP3 expression in stromal fibroblasts, attenuating antitumor immunity, and facilitating tumor invasion.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029661","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":"Tumor antigen PRAME promotes melanoma growth by inactivating p53 through the SIRT1-DBC1 axis","authors":"Yong-Kyu Lee,&nbsp;Hyeon Ho Heo,&nbsp;Ui-Hyun Park,&nbsp;HyeSook Youn,&nbsp;Eun-Joo Kim,&nbsp;Soo-Jong Um","doi":"10.1038/s41388-025-03565-z","DOIUrl":"10.1038/s41388-025-03565-z","url":null,"abstract":"Preferentially expressed antigen in melanoma (PRAME), which is highly expressed in melanoma, is associated with tumor progression and malignancy. Notably, melanoma cells often exhibit inactivation of the tumor suppressor p53 despite carrying the wild-type p53 gene. Here, we investigated the functional interplay between PRAME and p53. Consistent with our analysis of human databases, PRAME overexpression promoted melanoma cell proliferation. Conversely, PRAME downregulation produced the opposite effects, accompanied by an increase in apoptosis. RNA sequencing revealed aberrant regulation of p53 target genes following PRAME depletion, which was further supported by reverse transcription-quantitative polymerase chain reaction and luciferase reporter assays. To explore the underlying mechanism, we isolated the PRAME protein complex and identified DBC1, an SIRT1 suppressor, as a component of the complex. Furthermore, we observed that PRAME promoted p53 deacetylation. The interaction of PRAME with DBC1 releases SIRT1 from DBC1, enabling SIRT1 activation and subsequent p53 deacetylation. The combination of PRAME depletion and SIRT1 inhibition can significantly promote the growth retardation of melanoma cells, as demonstrated by xenograft analysis in nude mice. Collectively, these findings suggest that the acquired elevation of the PRAME level during melanoma pathogenesis may suppress p53 pathways, thereby promoting tumor growth. We propose that PRAME silencing combined with the use of SIRT1 inhibitors is a promising therapeutic strategy for melanoma by restoring p53 activity.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 42","pages":"4087-4099"},"PeriodicalIF":7.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023899","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":"Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG","authors":"Meenakshi Upreti,&nbsp;Astgik Petrosyan,&nbsp;Matthew E. Thornton,&nbsp;Anahit Hovsepyan,&nbsp;G. Esteban Fernandez,&nbsp;David S. Koos,&nbsp;Stephanie D. Byrum,&nbsp;Samuel G. Mackintosh,&nbsp;Jacob K. Al-Husseini,&nbsp;Tania Porras,&nbsp;Joseph Ha,&nbsp;Alan J. Tackett,&nbsp;Miqin Zhang,&nbsp;Malkiat S. Johal,&nbsp;Anat Erdreich-Epstein,&nbsp;Susan Durham,&nbsp;Mark D. Krieger,&nbsp;Ashley S. Margol,&nbsp;Brendan H. Grubbs,&nbsp;Timothy C. Chambers,&nbsp;Shahab Asgharzadeh,&nbsp;Rex A. Moats,&nbsp;Peter A. Chiarelli","doi":"10.1038/s41388-025-03533-7","DOIUrl":"10.1038/s41388-025-03533-7","url":null,"abstract":"It has become evident from decades of clinical trials that multimodal therapeutic approaches with focus on cell intrinsic and microenvironmental cues are needed to improve understanding and treat the rare, inoperable, and ultimately fatal diffuse intrinsic pontine glioma (DIPG), now categorized as a diffuse midline glioma. In this study we report the development and characterization of an in vitro system utilizing 3D Tumor Tissue Analogs (TTA), designed to replicate the intricate DIPG microenvironment. The innate ability of fluorescently labeled human brain endothelial cells, microglia, and patient-derived DIPG cell lines to self-assemble has been exploited to generate multicellular 3D TTAs that mimic tissue-like microstructures, enabling an in- depth exploration of the spatio-temporal dynamics between neoplastic and stromal cells. The 3D-TTA model recapitulates clinical patterns of DIPG growth, evidenced by resistance to chemotherapy, HDAC and proteasome inhibitors, as well as sensitization to the antibody-activated innate immune microenvironment including complement proteins and surrounding microglia. Multimodal fluorescence imaging platforms integrated with high-throughput omics revealed that alterations in tumor cell motility and growth in the 3D-TTA model compared to tumor cell only spheroids correlated with specific transcriptomic and proteomic changes. STAT3, ITGA5, LGALS1, SOD2, MVP, and CLIC1, associated with microenvironment signaling, DNA replication, and immune regulation, were identified as potential novel targets in the 3D model. The results indicate that the 3D TTA platform developed here represents a powerful tool for preclinical studies, paving the way for identification/validation of tissue specific biomarkers and novel drug targets, thus advancing disease management strategies for DIPG in children.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3694-3712"},"PeriodicalIF":7.3,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03533-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008389","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 FSP1 to induce ferroptosis in chromophobe renal cell carcinoma","authors":"Samer Salem,&nbsp;Tiegang Han,&nbsp;Michel Alchoueiry,&nbsp;Nadine Mahmoud,&nbsp;Wafaa Bzeih,&nbsp;Joelle Chami,&nbsp;Damir Khabibullin,&nbsp;Hadi Mansour,&nbsp;Yan Tang,&nbsp;Thai H. Ho,&nbsp;Jessalyn M. Ubellacker,&nbsp;Carmen Priolo,&nbsp;Elizabeth P. Henske","doi":"10.1038/s41388-025-03562-2","DOIUrl":"10.1038/s41388-025-03562-2","url":null,"abstract":"There are no proven therapies for metastatic or unresectable Chromophobe Renal Cell Carcinoma (ChRCC). ChRCC is characterized by high glutathione levels and hypersensitivity to ferroptosis, an iron-dependent form of cell death characterized by peroxidation of polyunsaturated fatty acids. The underlying mechanisms leading to ferroptosis hypersensitivity are unknown. Ferroptosis suppressor protein (FSP1) is a glutathione-independent suppressor of ferroptosis whose role in ChRCC is unexplored. In The Cancer Genomic Atlas (TCGA), we find that ChRCC exhibits the second highest upregulation of FSP1 relative to healthy organ out of all cancers, and that higher FSP1 expression correlates with poorer patient outcomes. We also define a ferroptosis signature combining FSP1 and Solute Carrier Family 7 Member 11 (SLC7A11) that predicts patient survival across all TCGA tumor types. Data queried from the Dependency Map and the Cancer Target Discovery and Development indicate that high FSP1 expression correlates with resistance to cell death induced by disruption of glutathione homeostasis via inhibition of glutathione peroxidase 4 (GPX4) or SLC7A11. Studies using ChRCC cell lines in vitro reveal that genetic inhibition of GPX4 or FSP1 individually does not induce substantial cell death, while inhibition of both results in near-complete loss of viability. Consistent with these genetic data, combining pharmacologic inhibition of GPX4 or SLC7A11 with inhibition of FSP1 demonstrates synergistic loss of viability. Strikingly, inhibition of FSP1 alone in vivo is sufficient to decrease ChRCC tumor growth by 69%, consistent with recent studies in lung and colorectal cancer showing similar effects. Taken together, these data establish FSP1 as targetable vulnerability in ChRCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 42","pages":"4075-4086"},"PeriodicalIF":7.3,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008356","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}