Cancer & Metabolism最新文献

{"title":"CYP8B1 suppressed by Ras/ERK leads to cholesterol accumulation and bile acids reduction and facilitates hepatic tumorigenesis.","authors":"Juan Li, Huiling Li, Lili Dong, Liang Yao, Xiaoying Dong, Yingyan Guo, Chunwen Pu, Aiguo Wang, Jun Chen","doi":"10.1186/s40170-026-00439-0","DOIUrl":"10.1186/s40170-026-00439-0","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol (CHO)/bile acids (BAs) homeostasis is critically involved in hepatocellular carcinoma (HCC), yet the underlying mechanisms and the specific regulatory role of CYP8B1-a key enzyme maintaining this balance-remain poorly defined. This study seeks to clarify the roles of CYP8B1 and its regulated CHO/BA homeostasis in the initiation and progression of HCC driven by aberrant RAS/ERK signaling.</p><p><strong>Method: </strong>Utilizing TCGA data analysis, clinical sample examination (including protein/mRNA level assessments and serum measurements), in vitro cell line studies, an HCC animal model (with histopathological classification and inhibitor treatments), and dietary interventions (a high-CHO diet and Taurodeoxycholic acid [TDCA, a main secondary BA] treatment) to investigate the roles of Ras/ERK and CYP8B1 in CHO/BA homeostasis and HCC progression.</p><p><strong>Results: </strong>Clinical HCC data and cell lines frequently show ERK hyperactivation with concomitant CYP8B1 reduction and CHO accumulation. In Hras12V transgenic mice (Ras-Tg), CHO was accumulated in hepatic tumor tissues (T), peri-tumoral tissues (P), and serum compared with wild-type (WT) mice, and this accumulation predominantly resulted from the attenuation of BA biosynthesis induced by reduced CYP8B1 activity. Inhibition of ERK activity by AZD6244 (a p-ERK inhibitor) notably elevated CYP8B1 activity and BAs levels and reduced CHO level in Ras-Tg. Further investigation revealed that SREBP2 is critically involved in the ERK-mediated regulation of CYP8B1 and CHO/BA homeostasis. Intriguingly, although CYP8B1 activity were extremely down-regulated in T compared with P, CHO was significantly lower in T than in P, and the combination of the extreme up-regulation of apolipoprotein (APO) A1 and APOB in T with disordered expression of serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) might reflect active efflux of CHO from hepatoma cells. Notably, further elevation of the CHO level with a high-CHO diet perturbed multiple signaling pathways (mTOR, NF-κB, GSK3β/β-catenin, caspase 3, and BAX/BCL2) and suppressed hepatic tumor progression but not tumorigenesis. Intriguingly, feeding TDCA significantly inhibits hepatic tumorigenesis and development by inhibiting ERK and mTOR pathways.</p><p><strong>Conclusion: </strong>CYP8B1 repressed by Ras/ERK plays crucial roles in CHO/BA homeostasis which facilitate hepatic tumor progression. These findings provide a novel theoretical foundation and therapeutic perspective for HCC treatment.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004459","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":"Gut microbiota-derived indole-3-propionic acid promotes lymph node metastasis in gastric cancer via the aryl-hydrocarbon receptor signaling pathway.","authors":"Mingfei Wang, Yan Wang, Mingshuai Bai, Qifan Peng, Qishuan Wu, Zhou Shang, Guangrui Chen, Zhengjun Zhang, Shilong Yang, Leping Li, Feng Tian, Changqing Jing","doi":"10.1186/s40170-026-00438-1","DOIUrl":"10.1186/s40170-026-00438-1","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiota (GM) regulates the tumor microenvironment through microbial metabolites. Indole 3-propionic acid (3-IPA) is one such metabolite that regulates gastrointestinal barrier function. In this study, we investigated the effects of 3-IPA on the progression of lymph node metastasis of gastric cancer (GC) and the molecular mechanisms that underlie them.</p><p><strong>Methods: </strong>The microbial metabolites were identified using a fecal metabolomic assay in GC patients. Lymphangiogenesis was evaluated using tube formation and wound healing assays in vitro. The expression of aryl hydrocarbon receptor (AHR), CYP1A1, and vascular endothelial growth factor receptor 3 (VEGFR3) were assayed using quantitative real-time PCR (qRT-PCR) and western blot (WB) analyses. Matrigel plug and popliteal lymph node metastasis model were employed to validate the influence on lymphangiogenesis and lymph node metastasis in vivo.</p><p><strong>Results: </strong>Fecal metabolomic and microbiome profiling was drastically different between GC patients with lymph node metastasis (GC-LM) and those without metastasis. The GC-LM group showed high 3-IPA expression in the feces; 3-IPA had no significant effect on GC cells; Human lymphatic endothelial cells showed greater tube formation and promoted migration after 3-IPA administration. Also, upregulation of AHR, CYP1A1, and VEGFR3 was observed. Moreover, administration of the AHR inhibitor suppressed tube formation and lymph node metastasis both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our findings suggest that gut microbiota-derived 3-IPA functions as a lymph node metastasis promoter through the AHR/CYP1A1-VEGFR3 axis in GC. 3-IPA could serve as a prognostic biomarker and conceivably a therapeutic target for GC lymph node metastasis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13359729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980833","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":"Normoxic HIFα-mediated metabolic rewiring in cancer as a novel therapeutic target of tumor heterogeneity.","authors":"Anaís Sánchez-Castillo, Jairo G E Lommen, Denise Consten, Kim Savelkouls, Lydie M O Barbeau, Kasper M A Rouschop, Marc A Vooijs, Kim R Kampen","doi":"10.1186/s40170-026-00433-6","DOIUrl":"10.1186/s40170-026-00433-6","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia-inducible factors (HIF1α, HIF2α) influence radiotherapy responses in non-small cell lung cancer (NSCLC) and glioblastoma (GBM), tumors characterized by oxygen and HIF expression heterogeneity. As the function of HIFs in normoxic metabolic function remained unexplored, we investigated how loss of HIF1α or HIF2α affects metabolism, redox homeostasis, and radiotherapy sensitivity in normoxia, aiming to identify opportunities for combined metabolic inhibition.</p><p><strong>Methods: </strong>NSCLC HIF1α or HIF2α knockout (KO) and HIFα wildtype (WT) models were analyzed using ¹³C-glucose mass spectrometry tracing before and after radiotherapy treatment. Metabolic phenotypes were validated using serine/glycine (ser/gly) synthesis enzyme expression by immunoblot and quantitative PCR, redox by ROS flow cytometry analysis, and DNA methylation by 5mC dot-blot assessment. Pharmacological inhibition of ser/gly metabolism was performed in both NSCLC and GBM models using the repurposed serine-glycine conversion inhibitor sertraline using incucyte confluency monitoring.</p><p><strong>Results: </strong>Both HIF1α and HIF2α KO cells displayed reduced glycolysis and compensatory ser/gly pathway hyperactivation. HIF1α KO cells channeled ser/gly into nucleotide (particularly TTP) synthesis and glutathione (GSH)-mediated antioxidant defense, conferring radiotherapy resistance. In contrast, HIF2α KO cells preferentially used serine for α-ketoglutarate (α-KG) production, the enhanced NADH/methionine-dependent redox system and the methionine cycle to support enhanced DNA methylation. Subsequently, following irradiation, only the radiation resistant HIF1α KO cells further enhanced ser/gly metabolism, increasing AMP/ATP and GSH/GSSG (oxidized GSH) ratios, whereas HIF2α KO cells failed to adapt and accumulated oxidative stress. HIF1α KO cells were more sensitive to pharmacological inhibition of ser/gly metabolism by sertraline, particularly in combination with irradiation, which abrogated their radioresistant phenotype in both NSCLC and GBM models.</p><p><strong>Conclusions: </strong>HIF1α-deficient cells rely on ser/gly synthesis for nucleotide production and antioxidant defense, promoting radiotherapy resistance while creating vulnerability to sertraline plus irradiation. HIF2α-deficient cells favor α-KG production and methionine-driven alternative redox and methylation pathways. Targeting ser/gly synthesis may overcome HIF-gradient-dependent radiotherapy resistance.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13162480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926571","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":"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":"10.1186/s40170-026-00436-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;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":5.9,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317265/pdf/","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":"OA","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":"<p><p>BACKGROUND: Fumarate hydratase (FH) is a crucial enzyme that converts fumarate to malate in the tricarboxylic acid cycle. FH dysregulation results in abnormal accumulation of oncometabolite fumarate, which drives susceptibility in fumarate hydratase-deficient renal cell carcinoma (FH-dRCC), but the precise mechanisms remain not fully understood. METHODS: Succinated proteins in UOK268 cells were identified by LC–MS/MS. FH wild-type and FH mutant cells were treated with ionizing radiation or hydroxyurea, and ATR-CHK1 activation was analyzed by Western blotting. Cell cycle distribution was assessed using a cell cycle arrest assay, and homologous recombination assay was performed to evaluate the efficiency of DNA double-strand break repair. Succination sites of replication protein A1 (RPA1) were determined by LC–MS/MS. RPA1 DNA-binding activity was examined by electrophoretic mobility shift assay. RESULTS: High fumarate levels impair activation of ATR-CHK1 signaling in response to replication stress and DNA damage. Mechanistically, fumarate modifies RPA1, an essential factor for ATR-CHK1 activation through succination, a post-translational modification. Succination of RPA1 occurs mainly at cysteine residues 481 and 486, which reduces its binding affinity for single-stranded DNA (ssDNA). RPA1 succination leads to deficient recruitment of TOPBP1 to ssDNA, resulting in attenuated CHK1 activation and defective cell cycle arrest in response to DNA damage. Succinated RPA1 compromises homologous recombination-mediated DNA repair. CONCLUSION: Our findings establish that fumarate-induced succination of RPA1 impairs DNA repair and cell cycle control, promoting genomic instability in FH-dRCC. This work reveals a novel mechanism by which oncometabolites contribute to genomic instability. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262520/pdf/","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":"OA","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":"10.1186/s40170-026-00434-5","url":null,"abstract":"<p><p>BACKGROUND: Aberrant cholesterol accumulation in diverse cancers is associated with intratumoral hypoxia, whereas the specific mechanistic connection underlying hypoxia-driven cholesterol metabolic dysregulation in prostate cancer (PCa) remains undefined. Our previous findings indicate that the positive feedback loop involving SUMO-specific protease 1 (SENP1) and hypoxia-inducible factor-1α (HIF-1α) is critical to maintaining hypoxia-mediated metabolic reprogramming, while whether SENP1 modulates hypoxia-driven cholesterol metabolism remains unclear. METHODS: Correlations among SENP1 expression, hypoxic status, and cholesterol metabolic profiles were analyzed using TCGA/GEO datasets, PCa tissue microarrays, and PCa cell lines. A series of molecular biology approaches, including co-immunoprecipitation, SUMOylation assay, proximity ligation assay (PLA), Western blotting, and luciferase reporter assay, were performed in HEK293T and PCa cells to clarify the regulatory mechanism of SENP1 in cholesterol metabolism. Patient-derived organoids (PDOs) and xenograft mouse models were utilized to evaluate the anti-tumor efficacy and safety of the SENP1 inhibitor Momordin Ic in vitro and in vivo. RESULTS: SENP1 expression was positively correlated with the expression of key cholesterogenic enzymes in PCa, and SENP1 was essential for hypoxia-induced intracellular cholesterol accumulation. Mechanistically, SENP1 directly catalyzed the deSUMOylation of sterol regulatory element-binding protein 2 (SREBP2) at the lysine 464 (K464) residue, which disrupted the interaction between SREBP2 and the E3 ubiquitin ligase FBXW7 and thereby stabilized the SREBP2 protein. Therapeutically, targeted inhibition of SENP1 by Momordin Ic significantly suppressed de novo cholesterogenesis, impaired the viability of PCa PDOs, and robustly inhibited tumor growth in xenograft models without inducing obvious systemic toxicity. CONCLUSION: Our study uncovers a previously unrecognized SENP1–SREBP2 regulatory axis that mediates hypoxia-induced de novo cholesterol biosynthesis in PCa, and identifies SENP1 as a promising therapeutic target for metabolic intervention in PCa treatment. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13231745/pdf/","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":"OA","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":"<p><p>BACKGROUND: Isocitrate dehydrogenase-wildtype glioblastoma (IDHwtGB) is the most common primary malignant brain tumor in adults, with a universally poor prognosis. For survival and growth under conditions of the tumor microenvironment, glioblastoma cells require antioxidant glutathione (GSH) and its metabolic precursor cystathionine (Cth) to maintain redox balance. We aimed to characterize GSH and Cth in vivo, in IDHwtGB patients, using edited MR spectroscopy (MRS). Our goal was to evaluate their tumor-molecular-status-dependent alterations and assess their potential as biomarkers for therapies targeting redox imbalance, following a reproducibility assessment of the measurement protocol in healthy subjects. METHODS: In this prospective study (January 2023 - July 2025), 5 healthy subjects and 27 patients with MRI-suspected glioma were scanned on a 3T MR scanner using single-voxel MEGA-sLASER MRS. Tumoral and contralateral metabolite concentrations were compared using linear mixed models. Associations between tumoral GSH and other metabolite concentrations, as well as tumor subregion fractions, were assessed via multiple linear regression. Spearman correlation was used to evaluate the association between GSH and p53 immunoreactivity. The GSH concentration was compared across MGMT status and molecular subtypes with the Wilcoxon rank-sum test. RESULTS: A good scan-rescan reproducibility was observed in metabolite quantification in healthy subjects. Fifteen patients with IDHwtGB and high-quality spectra (mean age 59 ± 11 years; 9 men) were included in the final analysis. Tumor tissue exhibited significantly elevated Cth (1.17 ± 1.30 mM vs. 0.63 ± 0.59 mM, p = 0.03) and lower gamma-aminobutyric acid levels (2.36 ± 0.70 mM vs. 3.04 ± 0.89 mM, p = 0.006) compared to contralateral. Tumoral GSH concentrations correlated positively with Cth (p < 0.001) and enhancing-tumor fraction (p < 0.001), and negatively with p53 accumulation (p = 0.008). No difference in GSH levels was observed with respect to MGMT status (p = 0.66), whereas lower GSH concentrations were found in the mesenchymal subtype (p = 0.04). CONCLUSIONS: GSH and Cth show promise as in vivo MRS biomarkers for therapies aimed at modulating redox balance. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00032097), retrospectively registered on 25 November 2024. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"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":"10.1186/s40170-026-00431-8","url":null,"abstract":"<p><p>OBJECTIVE: Hepatocellular carcinoma (HCC) poses a substantial health burden globally. We explored the mechanism of PFKFB4 affecting M2 polarization of tumor-associated macrophages (TAMs) in HCC. METHODS: The correlation between PFKFB4 expression and macrophage infiltration was analyzed by TIMER database. HCC and adjacent tissues from 30 HCC patients were collected to analyze the PFKFB4 positive expression rate, and the infiltration percentages of the M1- and M2-phenotype TAMs via immunohistochemistry and flow cytometry. PFKFB4 was knocked down or overexpressed in HCC cells, with cell glycolytic, proliferation, and migration assessed. M0 macrophages were co-cultured with HCC cells, with lactate level and TAM M2 polarization detected. H3K18 lactylation (H3K18la) level in TAMs, and its enrichment on the M2 polarization-related gene promoters (arginase 1 [Arg-1], CD206) were assessed by western blot and ChIP. Arg-1 and CD206 levels were tested by RT-qPCR and western blot. In vivo validations were performed in nude mice. RESULTS: PFKFB4 expression was increased in HCC, and was correlated with poor prognosis. The positive expression rate of PFKFB4 was positively correlated with M2-polarized TAM infiltration. PFKFB4 was up-regulated in HCC cells, which promoted the proliferation and migration of HCC cells via the glycolytic pathway and stimulated lactate production. Co-culture of TAMs with PFKFB4-overexpressing HCC cells promoted TAM M2 polarization. PFKFB4 stimulated tumor growth by promoting TAM M2 polarization via the glycolysis/lactate/H3K18la pathway in vivo. CONCLUSION: PFKFB4 promoted lactate accumulation in the tumor microenvironment via glycolysis, stimulated the H3K18la/M2 polarization regulatory axis in TAMs, thus regulating the immune microenvironment and promoting HCC growth. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182095/pdf/","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":"OA","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":"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":5.9,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185238/pdf/","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":"OA","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":"10.1186/s40170-026-00430-9","url":null,"abstract":"<p><p>Endometrial cancer (EC) is characterized by metabolic reprogramming, with cholesterol biosynthesis playing a critical role. However, the upstream transcriptional regulation of this process requires further elucidation. In this study, we identified POU2F1 as a key oncogenic transcription factor that drives cholesterol biosynthesis and tumor progression in EC. Integrative bioinformatics and clinical analyses revealed that POU2F1 is upregulated in EC and predicts poor prognosis. Mechanistically, POU2F1 directly activates DHCR24 and ELOVL2 transcription, thereby promoting DHCR24-mediated cholesterol biosynthesis and ELOVL2-associated lipid metabolic remodeling in EC. Functional assays demonstrated that POU2F1 promotes proliferation, migration, invasion, and xenograft growth in a DHCR24/ELOVL2-dependent manner. Clinically, POU2F1 expression was positively correlated with DHCR24 and ELOVL2 levels and served as an independent prognostic factor. Together, these findings establish the POU2F1-DHCR24/ELOVL2 axis as a critical driver of cholesterol-associated lipid metabolic reprogramming and cancer progression in EC, highlighting a potential therapeutic target for metabolic intervention.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188249/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}