Cancer & Metabolism最新文献

{"title":"BCAT1 inhibits glutamine-dependent Akt/mTOR signaling and nucleotide synthesis by initiating BTRC-mediated degradation of SLC3A2 in pancreatic adenocarcinoma.","authors":"Huimin Huang, Xinheng Liu, Xi Chen, Xinyi Tang, Hanxiang Qiu, Huajun Yu, Guihua Jin, Linhua Lan","doi":"10.1186/s40170-026-00436-3","DOIUrl":"https://doi.org/10.1186/s40170-026-00436-3","url":null,"abstract":"<p><strong>Purpose: </strong>Pancreatic adenocarcinoma (PAAD) is characterized by profound metabolic reprogramming, including altered branched-chain amino acid (BCAA) metabolism. While the tumor-promoting role of branched-chain aminotransferase 2 (BCAT2) in PAAD has been well documented, the function of branched-chain aminotransferase 1 (BCAT1) remains unclear, particularly in PAAD cells with low endogenous BCAT1 expression. This study aimed to define the context-dependent role of BCAT1 in PAAD and to elucidate the underlying molecular mechanisms.</p><p><strong>Methods: </strong>The expression of BCAT1 and BCAA metabolism-related molecules was assessed by Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of BCAT1 and SLC3A2 on PAAD cell proliferation were evaluated using CCK-8 assays in vitro and xenograft nude mouse models in vivo. Astral DIA proteomics and LC-MS-based untargeted metabolomics were performed to characterize protein and metabolic alterations induced by BCAT1 overexpression or SLC3A2 depletion. Stable SLC3A2-knockdown PAAD cell lines were established by lentiviral transduction. Seahorse XFe96 analysis was used to assess cellular bioenergetics by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR).</p><p><strong>Results: </strong>BCAT1 expression was markedly reduced in multiple PAAD cell lines, and ectopic BCAT1 overexpression significantly inhibited PAAD cell proliferation both in vitro and in vivo. Mechanistically, BCAT1 overexpression suppressed Akt/mTOR signaling, impaired mitochondrial respiration and glycolytic activity, and disrupted glutamine metabolism, glutathione metabolism, and nucleotide biosynthesis. Notably, intracellular BCAA levels were not significantly altered, whereas glutamine was markedly reduced. Glutamine supplementation partially rescued the BCAT1-induced inhibition of Akt/mTOR signaling and cell growth. Proteomic analysis further revealed that BCAT1 overexpression reduced SLC3A2 expression, and SLC3A2 depletion phenocopied the effects of BCAT1 overexpression on glutamine metabolism, bioenergetics, Akt signaling, and tumor growth. Mechanistically, BCAT1 promoted SLC3A2 degradation through a BTRC-dependent proteasomal pathway, thereby restricting glutamine uptake and reducing intracellular nucleotide availability.</p><p><strong>Conclusions: </strong>BCAT1 functions as a context-dependent tumor suppressor in PAAD. In BCAT1-low PAAD cells, BCAT1 overexpression inhibits tumor growth by promoting BTRC-dependent proteasomal degradation of SLC3A2, thereby limiting glutamine uptake and suppressing Akt/mTOR signaling, cellular bioenergetics, and nucleotide biosynthesis, despite minimal changes in intracellular BCAA levels. These findings identify the BCAT1-BTRC-SLC3A2 axis as a previously unrecognized metabolic regulatory pathway in PAAD and suggest a potential therapeutic strategy for targeting tumor metabolic vulnerabilities","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncometabolite fumarate impairs ATR-CHK1 signaling by succinating RPA1 in fumarate hydratase-deficient renal cell carcinoma cells.","authors":"Nian Liu, Changxian Shen, Tingting Zhou, Yu Zhou, Hang Yuan, Hongjie Bi, Yingying Wang, Xinyu Pei, Rui Su, Vijay Trisal, Li Zheng, Yihui Shi, Binghui Shen","doi":"10.1186/s40170-026-00435-4","DOIUrl":"10.1186/s40170-026-00435-4","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SENP1 drives de novo cholesterogenesis via disrupting SUMOylation-mediated SREBP2-FBXW7 interaction.","authors":"Chun Yang, Qingbo Wang, Bangmin Han, Xun Shangguan","doi":"10.1186/s40170-026-00434-5","DOIUrl":"https://doi.org/10.1186/s40170-026-00434-5","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo characterization of the redox balance in IDH-wildtype glioblastomas: a J-difference edited MEGA-sLASER MRS study at 3T.","authors":"Seyma Alcicek, Andrei Manzhurtsev, Dennis C Thomas, Iris Divé, Katharina J Weber, Vincent Prinz, Daniel Jussen, Dinesh K Deelchand, Georg Oeltzschner, Michael W Ronellenfitsch, Joachim P Steinbach, Elke Hattingen, Ulrich Pilatus, Katharina J Wenger","doi":"10.1186/s40170-026-00432-7","DOIUrl":"10.1186/s40170-026-00432-7","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13091267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PFKFB4 promotes M2 polarization of tumor-associated macrophages through aerobic glycolysis-mediated modification of histone H3K18 lactylation in hepatocellular carcinoma.","authors":"Chao Gan, Dan Wu, Yue Yuan, Lingling Li, Jia Bai, Yanmei Xu, Haihong Lv","doi":"10.1186/s40170-026-00431-8","DOIUrl":"https://doi.org/10.1186/s40170-026-00431-8","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining ferroptosis inducers with gemcitabine to enhance treatment efficacy in pancreatic cancer.","authors":"Hanyun Zhang, Wenjie Lu","doi":"10.1186/s40170-026-00423-8","DOIUrl":"https://doi.org/10.1186/s40170-026-00423-8","url":null,"abstract":"<p><strong>Background: </strong>Gemcitabine (GEM) is a standard chemotherapy for pancreatic cancer, but resistance limits its clinical benefit. The role of SRRM1, a splicing regulator, in GEM resistance remains unclear.</p><p><strong>Methods: </strong>The expression and prognostic significance of SRRM1 were analyzed in clinical datasets and validated by Western blotting and immunohistochemistry. GEM-resistant pancreatic cancer cell lines were established, and functional assays including colony formation, apoptosis, and CFDA staining were conducted to assess SRRM1's role in chemoresistance. RNA-seq and KEGG enrichment analyses were performed to explore downstream pathways. Ferroptosis was evaluated by C11-BODIPY staining, iron/MDA/GSH quantification, and mitochondrial function assays. NRF2's regulatory effect on SRRM1 was assessed using gain- and loss-of-function experiments. A pancreatic cancer xenograft model was used to validate the therapeutic relevance in vivo.</p><p><strong>Results: </strong>SRRM1 was significantly upregulated in pancreatic cancer and associated with poor prognosis and GEM resistance. Knockdown of SRRM1 suppressed tumor growth, enhanced GEM sensitivity, and induced ferroptosis, as evidenced by increased lipid peroxidation and mitochondrial damage. Rescue experiments confirmed the ferroptosis-suppressive function of SRRM1. Notably, we identified NRF2 as an upstream transcriptional activator of SRRM1, forming a pro-survival NRF2-SRRM1 axis that suppresses ferroptosis and promotes GEM resistance. Combining GEM with the ferroptosis inducer RSL3 yielded synergistic antitumor effects in vivo, especially in SRRM1-high tumors.</p><p><strong>Conclusion: </strong>This study suggests that SRRM1 may serve as a predictive biomarker for GEM response in pancreatic cancer. Targeting SRRM1 in conjunction with ferroptosis inducers could offer a promising strategy to overcome GEM resistance.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"POU2F1 drives cholesterol biosynthesis and lipid remodeling through the DHCR24/ELOVL2 axis in endometrial cancer.","authors":"Zi-Hui Zhang, Fei-Fei Yuan, Lian Yang, Wei Zhang, Shuang Li, Yu-Qin Huang","doi":"10.1186/s40170-026-00430-9","DOIUrl":"https://doi.org/10.1186/s40170-026-00430-9","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.","authors":"Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Matthew D Perricone, Heather Giza, Peter Sajjakulnukit, Amy L Myers, Zeribe C Nwosu, Jonathan M Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis","doi":"10.1186/s40170-026-00428-3","DOIUrl":"10.1186/s40170-026-00428-3","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13072669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurement of mitochondria amount and clearance using flow cytometry: effect of mitophagy inhibitors in leukemia cells.","authors":"Tereza Kořánová, Dana Grebeňová, Kateřina Kuželová","doi":"10.1186/s40170-026-00429-2","DOIUrl":"https://doi.org/10.1186/s40170-026-00429-2","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PER2 knockdown drives immunotherapy resistance in gastric cancer via metabolic reprogramming of myeloid-derived suppressor cells.","authors":"Shenggang Zhan, Shixi Lu, Feng Xiong, Haitao Li, Wenbiao Chen","doi":"10.1186/s40170-026-00424-7","DOIUrl":"https://doi.org/10.1186/s40170-026-00424-7","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}