Cancer & Metabolism最新文献

{"title":"Correction to: The role of deoxycholic acid in macrophage polarization and remodeling of the tumor microenvironment during colorectal adenoma-carcinoma transition.","authors":"Yujing Liu, Jie Yin, Lu Lu, Jiashu Pan, Gaoxuan Shao, Yangxian Xu, Guang Ji, Hanchen Xu","doi":"10.1186/s40170-026-00448-z","DOIUrl":"10.1186/s40170-026-00448-z","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879107","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":"PKM2 modulation regulates leukemia cell survival.","authors":"Nikolina Vrdoljak, Ekaterina N Parfenova, Alessia Roma, Drake A Mosca, Mark D Minden, Paul A Spagnuolo","doi":"10.1186/s40170-026-00440-7","DOIUrl":"10.1186/s40170-026-00440-7","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) cells exhibit aberrant metabolism defined by a shift away from oxidative phosphorylation and towards anaerobic glycolysis, favouring cell growth. Glycolytic enzymes are altered for this change to occur, including pyruvate kinase (PK), where the tetrameric and high activity M1 isoform (PKM1) is replaced with the predominantly dimeric and low activity M2 isoform (PKM2). Dimeric PKM2 produces less pyruvate and acts as a protein kinase in the nucleus, demonstrating divergent roles in both cell metabolism and as a transcriptional co-activator. In this study, the role of PKM2 in AML was defined, as PKM2 levels were elevated but PK enzymatic activity was reduced in AML cells compared to normal hematopoietic cells. Genetic and pharmacological studies show that decreasing and increasing PKM2 activity resulted in anti-AML effects both in vitro and in vivo. Indeed, these models show that inhibition and activation of PKM2 disrupt the native oligomeric state of the protein, resulting in reduced nuclear PKM2 accumulation and c-Myc expression, ultimately leading to cell death. Together, these results highlight the importance of PKM2 in AML, uncover the mechanisms by which both inhibition and activation cause AML cell death, and identify a novel modulator of PKM2 activity.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13499311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788238","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":"Caloric restriction enhances radiosensitivity of colorectal tumors through the cGAS-STING pathway activation.","authors":"Li-Li Zhang, Li-Qiang Qin, Li Ding, Wen-Yue Shan, Yu Zhao, Yu-Qi Zhang, Jia Gu, Lin Zhao, Kai-Yuan Hui, Yu-Song Zhang, Jia-Ying Xu","doi":"10.1186/s40170-026-00449-y","DOIUrl":"10.1186/s40170-026-00449-y","url":null,"abstract":"<p><p>Although radiotherapy is an important clinical option for colorectal cancer, its efficacy is limited by intrinsic tumor radioresistance and radiation-induced toxicity in surrounding normal tissues. This study investigated the radiosensitizing effects of either 7-day 30% caloric restriction (CR) or 24-hour fasting in a murine model bearing CT-26 colorectal tumor and explored the underlying mechanisms. CR and fasting pretreatment enhanced irradiation-induced tumor apoptosis, mitochondrial dysfunction, and cytosolic DNA stress, leading to activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS-STING) pathway, increased infiltration of tumor killing-associated CD8 + cytotoxic T lymphocytes, and modulation of macrophage polarization toward an antitumor phenotype. In addition, CR and fasting further suppressed the expression of glycolysis and lipid metabolism related proteins in the tumor microenvironment upon radiation exposure. By contrast, CR and fasting protected normal intestinal tissue from irradiation-induced damage. These findings were validated in vitro using CT-26 and normal small intestinal epithelial cells (IEC-6) cultured under medium with or without glucose. The critical role of the cGAS-STING pathway in enhancing radiosensitivity was confirmed through STING siRNA-mediated knockdown, combined with pharmacological intervention using the STING agonist MSA-2 and inhibitor H-151. In conclusion, our findings indicate that CR and fasting may increase the radiosensitivity of colorectal tumors, while reducing radiation injury to normal intestinal tissue.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547988","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":"VAV2 drives glycolytic reprogramming in esophageal squamous cell carcinoma via EIF3F-mediated MTA1 deubiquitination.","authors":"Weiling Liu, Yangyang Hou, Bo Wang, Fengna Liu, Lu Zheng, Hailing Wang, Shaomei Li, Xiaowan Zhou, Mengting Zhang, Shujun Yang, Yan Zhao","doi":"10.1186/s40170-026-00447-0","DOIUrl":"10.1186/s40170-026-00447-0","url":null,"abstract":"<p><p>Despite therapeutic advances, esophageal squamous cell carcinoma (ESCC) remains lethal due to metabolic adaptation via aerobic glycolysis. Here we report that VAV2 functions as an oncoprotein promoting this metabolic switch in ESCC. VAV2 overexpression enhances glycolytic flux-evidenced by increased glucose uptake, lactate production, and ECAR-while reducing oxygen consumption. Mechanistically, VAV2 upregulates EIF3F expression, enabling EIF3F to deubiquitinate and stabilize MTA1, which subsequently activates HIF-1α and its downstream targets GLUT1 and LDHA. EIF3F knockdown attenuates VAV2-driven oncogenic phenotypes and tumor progression in xenograft models, validating this axis as a functional dependency. This study uncovers a \"signaling-deubiquitination-metabolism\" regulatory nexus in ESCC and provides rationale for targeting VAV2-EIF3F interaction to overcome glycolysis-dependent therapy resistance.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419007","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":"Fasting-mimicking diet counteracts gut microbial dysbiosis in experimental lynch syndrome.","authors":"Lorena Garcia-Castillo, Giulio Ferrero, Olga Blaževitš, Giulia Francescato, Azra Thaseen Eliass, Natalia E Cortez, Marc Beltrà, Sonia Tarallo, Barbara Pardini, Paola Costelli, Alessio Naccarati, Valter D Longo, Fabio Penna","doi":"10.1186/s40170-026-00446-1","DOIUrl":"10.1186/s40170-026-00446-1","url":null,"abstract":"<p><p>The development of colorectal cancer (CRC) is largely influenced by hereditary factors, with up to one-third of cases linked to genetic predisposition. In parallel, environmental factors such as diet and intestinal microbiota play a significant role. Lynch syndrome (LS), the most common form of hereditary CRC, is due to mutations in DNA mismatch repair genes. Diet interventions such as calorie restriction (CR) can modify the course of the disease, altering nutrient supply and promoting beneficial microbial populations. Fasting-mimicking diets (FMD) are plant-based CR regimens that showed promise in modulating the gut microbiota and suppressing CRC progression in pre-clinical ectopic cancer models. In this study, Villin-Cre/Msh2-floxed (VCM) mice, modelling LS, were subjected to periodic FMD cycles for 10 months. FMD regimen influenced animal weight in a sexually dimorphic manner, stably reducing animal body weight only in males. Moreover, shotgun metagenomic sequencing revealed that FMD mitigated the dysbiotic longitudinal changes associated with cancer onset, preserving beneficial species, such as Lactobacillus johnsonii, and reducing adverse species, such as Escherichia coli. Metabolic pathway analysis also showed significant differences, with FMD preventing the upregulation of pathways involved in amino acid and nucleotide synthesis, potentially promoting tumour growth. Overall, the findings suggest that periodic FMD may result useful in a multimodal approach for LS management, counteracting gut microbiota alterations.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359591","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":"CRISPR screen identifies autophagy inhibition (GNS561) as a PARP inhibitor (AZD5305) combination strategy in small cell lung cancer.","authors":"Tony Yu, Ranya Barayan, Lifang Song, Vidhyasagar Venkatasubramanian, Janvi Tamakuwala, Sree N Nair, Vivek Philip, Benjamin H Lok","doi":"10.1186/s40170-026-00443-4","DOIUrl":"10.1186/s40170-026-00443-4","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung cancer (SCLC) is a deadly cancer with few treatment options and poor prognosis, creating a dire need for improving therapies. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been tested as a treatment strategy, but patient response varies. We aimed to identify novel approaches to sensitize SCLC to PARPi through a genome-wide CRISPR dropout screen.</p><p><strong>Methods: </strong>Genome-wide CRISPR dropout screening was conducted in two SCLC cell lines using the PARPi, olaparib, as the selection pressure. Stable shRNA-mediated knockdown cell lines were validated by Western blotting and tested for olaparib sensitivity by assaying for cell viability. Synergy between PARPi and autophagy inhibition was tested by treating SCLC cell lines and analyzing cell viability using SynergyFinder+. The therapeutic strategy combining AZD5305 (PARPi) and GNS561 (novel autophagy inhibitor) was tested in cell line-derived xenograft mouse models.</p><p><strong>Results: </strong>CRISPR screening identified the loss of mTOR negative regulators as a mechanism of PARPi sensitivity in SCLC, and knockdown of TSC1 and TSC2 sensitized SCLC cell lines to olaparib. Therapeutic strategies combining PARPi and autophagy inhibition demonstrated synergy in SCLC cell lines, and combination therapy with AZD5305 and GNS561 was effective in cell line-derived xenograft mouse models.</p><p><strong>Conclusions: </strong>Autophagy inhibition downstream of the mTOR pathway is a mechanism of PARPi sensitivity in SCLC. This suggests that a therapeutic combination of autophagy inhibition and PARPi is a promising treatment strategy in SCLC, paving the way for the adoption of novel treatments in this disease context.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307168","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":"Identification of alpha1-oleate as a potent regulator of adipokine-dependent metabolism, in bladder cancer tissue.","authors":"Farhan Haq, Siddharth Chinchankar, Ines Ambite, Shahram Ahmadi, Hien Tran, Atefeh Nazari, Antonin Brisuda, Jaromir Hacek, Marek Babjuk, Catharina Svanborg","doi":"10.1186/s40170-026-00445-2","DOIUrl":"10.1186/s40170-026-00445-2","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunctions are associated with increased cancer morbidity and rapid tumor progression. The alpha1-oleate complex has been used successfully to treat bladder cancer in a placebo-controlled Phase II study. Studies of the related BAMLET complexes recently identified effects on metabolism, suggesting additional functions of the \"HAMLET family\" of tumoricidal complexes.</p><p><strong>Aims: </strong>To investigate if intravesical alpha1-oleate treatment affects metabolism in bladder cancer tissue.</p><p><strong>Materials and methods: </strong>Samples were obtained from patients with NMIBC, enrolled in a placebo-controlled study of intravesical alpha1-oleate treatment [1]. Cells shed into the urine were harvested at each instillation and biopsies obtained at TURBT after six instillations of alpha1-oleate. The shed cells and biopsies were subjected to RNA sequencing and genome-wide transcriptomic analysis, and urine samples were analyzed using adipokine arrays.</p><p><strong>Results: </strong>RNA sequencing detected significant inhibition of metabolic genes and networks in shed cells and tissue biopsies from alpha1-oleate treated patients, compared to the placebo group. Genes and gene networks regulating glucose and lipid synthesis were inhibited in alpha1-oleate treated patients, including ADIPOQ, which encodes the lipid- and glucose-regulating protein adiponectin and LEP, which encodes the metabolism and fat storage regulator Leptin. Leptin was further identified as an upstream regulator of the adiponectin response to alpha1-oleate and LEP and ADIPOQ networks showed strong interconnection in treated tissues. Analysis of shed tumor cells, suggested rapid kinetics of the metabolic response and urine levels of adiponectin and leptin were increased post-treatment, compared to pre-treatment samples and the shed tumor cells in urine contained adiponectin and leptin, as shown by immunohistochemistry.</p><p><strong>Conclusions: </strong>The findings identify potent local effects of alpha1-oleate treatment on tumor metabolism, after intravesical instillation. The metabolic regulators adiponectin and leptin were affected in tumor tissue and cells containing adiponectin and leptin were shed into the urine, potentially depleting the tumor of cells with high adipokine levels. These potent effects suggest a new molecular approach for targeting and inhibiting key regulators of cancer metabolism in superficial tumors.</p><p><strong>Trial registration: </strong>Doubleblinded Phase I/II clinical trial (EudraCT 201600426914 NCT03560479, Registration Date 20180521).</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307158","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":"DLL1-mediated ferroptosis resistance via the Notch-Nrf2/GPX4 axis drives cisplatin resistance in ovarian cancer.","authors":"Dan Ye, Gaoting Huang, Xingcheng Yan, Lezi Suntan, Haoran Shen, Jian Shen","doi":"10.1186/s40170-026-00444-3","DOIUrl":"10.1186/s40170-026-00444-3","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OV) is a leading cause of cancer-related mortality, with cisplatin resistance being a major clinical challenge. This study investigates the role of the Notch ligand DLL1 in mediating ferroptosis resistance and its impact on cisplatin sensitivity in OV.</p><p><strong>Methods: </strong>Multi-omics data, clinical samples, and OV cell lines were used to assess DLL1 expression, its link to prognosis, and its effect on the Nrf2/GPX4 axis. CCK-8, clone formation, and ferroptosis assays evaluated the impact of DLL1 on cell behavior and cisplatin sensitivity.</p><p><strong>Results: </strong>DLL1 was upregulated in OV tissues and correlated with poor prognosis. Its knockdown inhibited cell proliferation, migration, and EMT, while inducing ferroptosis, evidenced by increased lipid peroxidation and mitochondrial dysfunction. Mechanistically, DLL1 activated the Nrf2/GPX4 antioxidant axis. DLL1 depletion sensitized OV cells to cisplatin. In vivo, combining DLL1-targeted therapy with a ferroptosis inducer significantly reduced tumor growth in cisplatin-resistant models.</p><p><strong>Conclusion: </strong>DLL1 drives cisplatin resistance in OV by enhancing ferroptosis resistance via the Notch-Nrf2/GPX4 axis. Targeting DLL1 alongside ferroptosis induction represents a promising therapeutic strategy, positioning DLL1 as a potential biomarker and target in drug-resistant OV.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270363","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":"Fine particulate matter and tobacco product exposure exacerbates metabolic syndrome-related colon cancer via regulating oxidative stress and tumor-associated macrophage interactions.","authors":"Shenghua Zhang, Dongfang Meng, Haibo Zhang, Fei Pan, Yongsheng Gao, Jijin Wang","doi":"10.1186/s40170-026-00442-5","DOIUrl":"10.1186/s40170-026-00442-5","url":null,"abstract":"<p><strong>Background: </strong>The incidence of colorectal cancer (CRC) is closely associated with prolonged exposure to fine particulate matter (PM 2.5) and tobacco carcinogens, 4-methylnitrosamino-l-3-pyridyl-butanone (NNK). However, due to a lack of understanding of its intricate pathological processes, there is currently no approved clinical medication or successful treatment plan. Also, tobacco carcinogens and PM 2.5 are implicated in the progression of CRC by the onset of a metabolic disorder. Nonetheless, direct evidence connecting the metabolic disorder to NNK/PM 2.5-mediated CRC development has yet to be developed.</p><p><strong>Methods: </strong>We investigated CRC cells treated with NNK/PM 2.5 to investigate the function of metabolic alterations in CRC (NNK/PM 2.5)-induced tumor growth. The results were verified using human CRC cancer samples, cell-derived xenografts, and online survival analysis. To clarify the mechanism of regulation of changes in metabolism, metabolic tracking, western blotting, massarray assay, real-time PCR, and reporter assays were conducted. SPSS version 20.0 or GraphPad Prism version 10.0 were used for all statistical analyses.</p><p><strong>Results: </strong>Our research indicates that NNK/PM 2.5, elicit characteristics of metabolic syndrome, notably hyperglycemia, decrease in reactive oxygen species (ROS) contents, and a substantial upregulation of anti-oxidative stress-related gene expression, thereby facilitating the progression of colon cancer in a murine model. By increasing the expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1), NNK/PM 2.5 increases the uptake of glucose in tumor-associated macrophages. This leads to the increased expression of insulin-like growth factor 2 (IGF2), which in turn paracrinely hyper-activates the insulin receptor (IR) in colorectal cancer cells, facilitating its nuclear import. Through IR/NPM1 mediation, nuclear IR and nucleophosmin (NPM1) interact to activate the CD274 promoter and produce programmed death ligand-1 (PD-L1). Inhibiting glycolysis, diminishing macrophages, or obstructing PD-L1 impedes NNK/PM 2.5-induced colorectal cancer growth. Analysis of patient samples and public databases reveals elevated expression of tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR), as well as elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, suggesting possible negative prognostic biomarkers for patients with colorectal cancer.</p><p><strong>Conclusions: </strong>Our results provided new insights into the mechanisms of intestinal cancer progresses by paracrine IR-PD-L1 signaling, which is aided by the deregulation of oxidative stress and macrophage communication brought on by smoking carcinogen-induced the metabolic syndrome.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263485","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":"A method utilizing chemical carcinogens and a Western diet to reliably induce advanced hepatocellular carcinoma in male and female mice.","authors":"Melina C Mancini, Elise R Adams, David H Burk, Richard P Carmouche, Sara M Webb, Jaroslaw Staszkiewicz, J Michael Salbaum, Samuel G Mackintosh, Timothy D Heden","doi":"10.1186/s40170-026-00441-6","DOIUrl":"10.1186/s40170-026-00441-6","url":null,"abstract":"<p><strong>Background: </strong>A combination of chemical carcinogens and Western diet have been used to induce hepatocellular carcinoma (HCC) in mice, but these models show low incidence of HCC in female mice, while mice that do develop HCC show a wide range of HCC stage development. Therefore, a more reliable method that induces advanced stage HCC in both male and female mice is warranted. The purpose of this study was to create a simple, yet tolerable and reliable method that utilizes chemical carcinogens and a Western diet to induce advanced stage HCC in both male and female mice.</p><p><strong>Methods: </strong>Mice were provided with a low-fat control diet or Western diet at weaning and for the remainder of their 30-week lifetime. To induce HCC, mice given the Western diet received the sequential administration of low dose diethylnitrosamine (DEN), thioacetamide (TAA), and sucrose water.</p><p><strong>Results: </strong>This method produced stage 2-3 HCC by 30 weeks of age in 100% of male mice and 96% of female mice (4% had stage 1 HCC), with a low fatality rate. Spatial transcriptomics, proteomics, and western blotting revealed this method alters gene and protein markers of HCC in a similar fashion compared to human HCC.</p><p><strong>Conclusions: </strong>This study introduces a new method that utilizes chemical carcinogens and a Western diet to reliably induce advanced HCC in both male and female mice. Importantly, the method was tolerable while the HCC model is translational as it induced protein and gene signatures comparable to human advanced HCC. This new method provides a valuable HCC model that can be used to better understand the pathogenesis of HCC or for preclinical testing of new therapeutic approaches to treat advanced HCC.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210236","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}