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Background: Metastasis and chemoresistance are often major challenges in advanced-stage colorectal cancer. Bufalin has a therapeutic effect on both metastasis and drug resistance, but how bufalin affects chemoresistance-mediated metastasis remains unclear., Methods: The role of BU in the inhibition of EMT and angiogenesis induced by chemoresistant cells using wound healing assays, invasion assays, HUVEC tube formation and adhesion assays. Western blot and immunofluorescence were used to explore the potential molecular changes. BU can precisely regulate c-Myc expression by targeting SRC-3 in chemoresistant cells was confirmed by Western blot. In vivo experiments were conducted to validate that both BU and cinobufacini can ameliorate drug resistance-promoted EMT and angiogenic effects., Results: Bufalin inhibited resistance-induced epithelial-mesenchymal transition (EMT) and angiogenesis. Targeting of the SRC-3 protein by bufalin reduced the expression level of c-Myc and inhibited the prometastatic effect mediated by chemoresistance, and overexpression of SRC-3 or c-Myc reversed the inhibitory effect of bufalin on chemotherapeutic resistance, promoting metastasis. Moreover, the clinical drug cinobufacini and its main active monomer bufalin reduced liver metastasis of colorectal cancer caused by chemoresistance in vivo., Conclusion: Bufalin can target the SRC-3/c-Myc signaling pathway to affect the prometastatic effect of chemoresistant cells, suggesting that bufalin may be used as a new adjuvant antimetastatic therapy for colorectal cancer., Competing Interests: Declarations. Ethical approval: All patient samples were obtained after informed consent and approval of the ethics committee of Putuo District Center Hospital, Shanghai (Putuo Hospital, Shanghai University of Traditional Chinese Medicine). All animal experiments were conducted in accordance with guidelines and protocol approved by the institutional animal care and use committee of Putuo Hospital, Shanghai University of Traditional Chinese Medicine, China. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Hepatic stellate cells (HSCs) transdifferentiate into myofibroblasts during liver fibrosis and exhibit increased glycolysis. Phosphorylated focal adhesion kinase (FAK) (pY397-FAK) promotes monocarboxylate transporter 1 (MCT-1) expression in HSCs to increase aerobic glycolysis and cause liver fibrosis. A combined multiomics analysis of C57BL/6 mice with tetrachloromethane (CCl 4 )-induced liver fibrosis was performed to identify the downstream FAK signaling pathway. The effect of the FAK inhibitor PF562271 on CCl 4 -induced liver fibrosis was explored by immunofluorescence of liver tissues. The migration, proliferation and aerobic glycolysis of LX-2 cells after stimulation and activation by transforming growth factor beta-1 (TGF-β1) or suppression by PF562271 was assessed in vitro. Multiomics analysis of a successfully generated CCl4-induced liver fibrosis mouse model was performed. FAK and cyclin D1 were significantly enriched in mice with CCl4-induced liver fibrosis. In vivo, the MCT-1 and alpha smooth muscle actin (α-SMA) levels were increased in mice with CCl4-induced liver fibrosis, and MCT-1 and α-SMA expression decreased after PF562271 treatment. In vitro, PF562271 alleviated TGF-β1-induced LX-2 activation. LX-2 cells showed diminished migration, proliferation, and aerobic glycolysis after PF562271 intervention. FAK promotes aerobic glycolysis in LX-2 cells through the cyclin D1/c-Myc/MCT-1 pathway, thereby increasing liver fibrosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Institutional Review Board statement: This study was reviewed and approved by the Institutional Review Board of the Affiliated Hospital of Guizhou Medical University (Approval 2018 Ethics Review No. 032). Institutional animal care and use committee statement: Animal care and experimental procedures were authorized by the Animal Ethics Committee of Guizhou Medical University (No. 1801109)., (© 2025. The Author(s).)

Hepatocellular carcinoma (HCC), known for its high malignancy, exhibits a critical feature in its progression through the alteration of metabolic pathways. Our study initially observed an increase in hyaluronic acid (HA) secretion by HCC cells through ELISA analysis. Further protein-protein interaction (PPI) network analysis highlighted CD44 and HAS2 as critical nodes, suggesting their pivotal roles in HA metabolism. Silencing of HAS2 markedly reduced HA production and suppressed cell proliferation, whereas overexpression of HAS2 enhanced HA synthesis and promoted cellular growth. Moreover, we found that HA, through binding to CD44, activates the downstream PI3K/AKT/MYC signaling pathway. This activation not only upregulates MYC expression but also leads to an increase in GLUT1 expression level. As a transcription factor for GLUT1, MYC directly facilitates its expression, thereby enhancing glucose uptake and glycolytic activity. Additionally, CD44 can directly interact with GLUT1, further promoting glucose flux. These mechanisms collectively boost anaerobic glycolysis and the hexosamine biosynthetic pathway (HBP), providing essential energy and metabolites for rapid liver cell proliferation. Our findings not only elucidate the central role of HA in regulating cellular metabolism but also lay a solid theoretical foundation for developing therapeutic strategies targeting HA-related metabolic pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer., Methods: The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting., Results: Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs., Conclusions: UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies., Competing Interests: Declarations. Conflict of interest: The authors declare there is no conflict of interest., (© 2024. The Author(s).)

MYC-driven medulloblastomas (MB) are highly aggressive pediatric brain tumors with poor outcomes, and effective therapies remain limited despite intensive multimodal treatments. Targeting MYC directly is challenging, but exploiting MYC-mediated synthetic lethality holds promise. In this study, we investigated the combined effects of EZH2 and PARP inhibitors in MYC-high medulloblastoma and demonstrated that EZH2 inhibition significantly increased the sensitivity of MYC-high MB tumor cells to PARP inhibitors. This effect occurs through the upregulation of NUPR1, which promotes error-prone non-homologous end-joining (NHEJ) DNA repair by facilitating the recruitment of the XRCC4-LIG4 complex to DNA damage sites. This amplification of error-prone NHEJ DNA repair leads to genetic instability and eventual cell death in cells treated with the PARP inhibitor. The synergistic effect of EZH2 and PARP inhibitors was further validated in both in vitro and in vivo MB models without observed toxicity. These findings reveal a novel therapeutic strategy for MYC-high MB by co-targeting EZH2 and PARP, suggesting that this combination could potentially overcome the clinical challenges associated with this aggressive tumor subtype and warrants further investigation in clinical trials., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: MB tissue specimens were obtained from the Children’s Hospital of Fudan University after approval by the ethics review board of the hospital. All patients were informed, and consent was obtained. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Children’s Hospital of Fudan University. Consent for publication: The authors consent to publish the paper., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC-driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. In this study, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase promoter led to a preponderance of PDX1+ somatostatinoma, a type of pancreatic neuroendocrine tumor. However, c-MYC activation via an improved Cre recombinase driven by a dopamine β-hydroxylase promoter resulted in neuroblastoma development. The c-MYC murine neuroblastoma tumors recapitulated the pathologic and genetic features of human neuroblastoma and responded to anti-GD2 immunotherapy and difluoromethylornithine, an FDA-approved inhibitor targeting the MYC transcriptional target ODC1. Thus, c-MYC overexpression results in different but related tumor types depending on the targeted cell. The GEMMs represent valuable tools for testing immunotherapies and targeted therapies for these diseases. Significance: The development of c-MYC-driven genetically engineered neuroblastoma and somatostatinoma mouse models provides useful tools for understanding the tumor cell origin and investigating treatment strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Anaplastic thyroid cancer (ATC) is a highly lethal form of thyroid cancer. lysine acetyltransferase 5 (KAT5) has been found to promote ATC development via c-Myc stabilization by previous study. We thus designed experiments to confirm the anti-tumor effect of a KAT5 inhibitor (MG149) in ATC., Methods: Western blotting assessed the level of KAT5, c-Myc, and epithelial-mesenchymal transition (EMT)-related proteins in ATC cells and xenograft tumor tissues. Cell counting kit-8, flow cytometry, wound healing, and transwell assays revealed the effect of MG149 on cell proliferation, apoptosis, migration, and invasion in ATC cell lines. Immunofluorescence detected the level of E-cadherin and N-cadherin in ATC cell lines. The effect of MG149 on KAT5-mediated c-Myc stabilization was detected using co-immunoprecipitation assay. Tumor volume and tumor weight in ATC xenograft models were evaluated. H&E staining showed the effect of MG149 on lung metastasis in vivo. We further investigated whether MG149 can enhance the sensitivity of ATC to cisplatin (CDDP)., Results: MG149 inhibited cell proliferation and increased the apoptosis of cells. MG149 suppressed the migratory and invasive ability of ATC cells. The EMT in CAL-62 and 8505C cells was significantly inhibited by MG149. MG149 suppressed the KAT5-mediated c-Myc acetylation. MG149 inhibited tumor growth and lung metastasis in vivo. Additionally, MG149 potentiated the sensitivity to CDDP in ATC cells in vitro and in vivo., Conclusion: MG149 suppresses ATC progression and metastasis by inhibiting the acetylation of c-Myc mediated by KAT5., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Tumor metabolic reprogramming, particularly involving mitochondrial metabolism, is a hallmark of malignancy. The mitochondrial protein p32 (C1QBP) has emerged as a critical regulator in various cancers, frequently associated with poor patient prognosis. However, the role of p32 across different cancer types remains largely unexplored. Our bioinformatics analysis demonstrates that p32 is significantly overexpressed in several malignancies and is closely involved in multiple oncogenic pathways related to tumor progression and metabolic reprogramming. Moreover, p32 expression positively correlates with genomic heterogeneity and drug sensitivity. We identified a strong association between p32 and c-Myc in both normal and cancerous tissues. We confirmed that p32 is a direct transcriptional target of c-Myc, which upregulates p32 by binding to its promoter. Functional experiments established that p32 is crucial for MYC-driven tumorigenesis, with its knockdown or knockout inhibiting tumor proliferation and extending survival. Targeting p32 may inhibit MYC-driven tumorigenesis, highlighting its potential as a therapeutic target in MYC-driven cancers., Competing Interests: Declarations. Competing interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Endometrial cancer (EC) is a prevalent gynecologic malignancy. The critical role of PTPN18 in EC has been reported, while its role in the aerobic glycolysis of EC cells remains unclear. Our current study focused on the mechanism of PTPN18 in the regulation of aerobic glycolysis in EC., Methods: PTPN18 expression levels in endometrial stromal cells (KC02-44D) and EC cells (KLE, HEC-1-A, HEC-1B, and HEC-50) were determined. Following transfection of sh-PTPN18 in HEC-1-A cells, the changes in cell migratory and invasive abilities were assessed by the Transwell assay, and the changes in glucose consumption, lactic acid secretion, and ATP levels were detected using kits. The expression levels of glycolysis-related proteins HIF-1α, PKM2, and LDHA and the activation of the MYC/PI3K/AKT pathway were detected by Western blot. Additionally, sh-PTPN18 and pcDNA3.1-MYC were transfected into HEC-1-A cells to further explore their roles in the changes in aerobic glycolysis, migration, and invasion ability of EC cells., Results: Expression of PTPN18 in EC cells was up-regulated (HEC-1-A>HEC-1B>HEC-50>KLE). PTPN18 knockdown suppressed EC cell migration and invasion. Additionally, PTPN18 knockdown reduced glucose consumption, lactate production, ATP levels, and glycolysis-related protein levels (HIF-1α, PKM2, LDHA). PTPN18 knockdown inhibited the activation of the MYC/PI3K/AKT pathway in EC cells. MYC overexpression partially annulled the inhibitory effects of PTPN18 knockdown on aerobic glycolysis, migration, and invasion of EC cells., Conclusion: Our present study provided evidence that the knockdown of PTPN18 inhibited the aerobic glycolysis, migration, and invasion of EC cells by suppressing the MYC/PI3K/AKT pathway., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Epstein-Barr virus (EBV) is the first human cancer-causing viral pathogen to be discovered; it has been epidemiologically associated with a wide range of diseases, including cancers, autoimmunity, and hyperinflammatory disorders. Its evolutionary success is underpinned by coordinated expression of viral transcription factors (EBV nuclear antigens), signaling proteins (EBV latent membrane proteins), and noncoding RNAs, which orchestrate cell transformation, immune evasion, and dissemination. Each of those activities entails significant metabolic rewiring, which is achieved by viral subversion of key host metabolic regulators such as the mammalian target of rapamycin (mTOR), MYC, and hypoxia-inducible factor (HIF). In this review, we systemically discuss how EBV-encoded factors regulate metabolism to achieve viral persistence and propagation, as well as potential research questions and directions in EBV-driven metabolism., (© 2025 Wiley Periodicals LLC.)

Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a crucial serine-threonine kinase involved in the process of cell mitosis. However, the precise relationship between NEK2 and esophageal squamous cell carcinoma (ESCC) remains inadequately understood. NEK2 expression in ESCC tissues was assessed through bioinformatics analysis, reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry, revealing a correlation with ESCC patient prognosis. Cultured ESCC cells and human normal esophageal epithelial cells (HEEC) were used to investigate the effects of NEK2 knockdown on the development and progression of ESCC by integrated confluence algorithm, colony formation, wound-healing, transwell, and ESCC xenograft tumor model, in vitro and in vivo. In ESCC tissues, NEK2 was found to be significantly upregulated, and its expression correlated with poor prognosis in ESCC patients. NEK2 may facilitate ESCC development by regulating cell proliferation, migration, and invasion. Additionally, results from in vivo experiments suggested that NEK2 knockdown can inhibit tumor growth. Moreover, forkhead box M1 (FOXM1) was identified as a potential downstream target of NEK2 in the regulation of ESCC, with its overexpression reversing the effects of NEK2 knockdown on ESCC. Mechanistic studies also indicated that NEK2 may promote the malignant progression of ESCC by inhibiting cellular senescence through the activation of the FOXM1/c-Myc/p27 signaling pathways, which may provide a novel perspective for the management of ESCC., (© 2024 Wiley Periodicals LLC.)

Background & Aims: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aimed to determine the significance of diacyltransferases (diacylglycerol o-acyltransferases 1 and 2 [DGAT1/2]), responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis., Methods: Human colon cancer samples, colon cancer cells, colonospheres, and Apc Min/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and small interfering RNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analyses of CUT&RUN and RNA sequencing data were performed., Results: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs nontransformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and accumulation of LDs, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in Apc Min/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in patients with colon cancer., Conclusions: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, providing a platform for future development of effective treatments for patients with colon cancer., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Significance: We show that HSF1 and MYC genes are co-amplified in more than 30% of HGSOC and demonstrate that HSF1 and MYC functionally cooperate to drive the growth of HGSOC cells. This work provides the foundation for HSF1 and MYC co-amplification as a biomarker for treatment efficacy of the polo-like kinase 1 inhibitor volasertib in HGSOC., (©2025 The Authors; Published by the American Association for Cancer Research.)

Introduction: MYC overexpression is a known phenomenon in breast cancer. This study investigates the correlation of MYC gene copy number amplification and MYC protein overexpression with coexisting genetic abnormalities and associated clinicopathologic features in breast cancer patients., Methods: The study analyzed data from 81 patients with localized or metastatic breast cancers using targeted next-generation sequencing and MYC immunohistochemical studies, along with pathological and clinical data., Results: Applying the criteria of MYC /chromosome 8 ratio ≥5, MYC copy number amplified tumors (n = 11, 14%) were associated with invasive ductal carcinoma (91% vs 68%, P  = .048), poorly differentiated (grade 3, 64% vs 30%, P  = .032), mitotically active (Nottingham mitotic score 3, 71% vs 20%, P  = .004), estrogen receptor (ER)-negative (45% vs 12%, P  = .008), and triple-negative (56% vs 12%, P  = .013) compared to MYC non-amplified tumors. Among MYC -amplified breast cancer patients, those with triple-negative status showed significantly shorter disease-free survival time than non-triple negative MYC -amplified patients (median survival month: 25.5 vs 127.6, P  = .049). MYC amplification is significantly associated with TP53 mutation ( P  = .007). The majority (10 of 11; 91%) of MYC -amplified tumors showed positive c-MYC immunostaining., Conclusion: Breast cancers with MYC copy number amplication display distinct clinicopathologic characteristics indicative of more aggressive behavior., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background Aim: Breast cancer is a prevalent and aggressive malignancy associated with elevated mortality rates worldwide. Dysregulation of the c-MYC oncogene and aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway are common features in breast cancer progression, rendering them attractive therapeutic targets. Here, we assessed the effects of the plant derivative, xanthine, on breast cancer cells and explored the molecular mechanisms underlying its activity., Methods: Breast cancer cell lines were treated with xanthine, followed by assessment of c-MYC expression levels. Cell proliferation, invasion, and migration were analyzed to assess the effects of xanthine treatment on breast cancer cell behavior., Results: Xanthine treatment induced a decrease in c-MYC expression, resulting in significant inhibition of breast cancer cell proliferation, invasion, and migration. Mechanistic investigations revealed that these effects were mediated by suppression of the PI3K/AKT signaling pathway., Conclusions: Xanthine shows great potential for breast cancer treatment by targeting c-MYC via the PI3K/AKT signaling pathway. Our findings indicate that development of xanthine as a novel treatment option for breast cancer, which acts by influencing key oncogenic pathways involved in tumor progression, may be warranted., (© 2024 John Wiley & Sons Australia, Ltd.)

Pancreatic cancer ranks fourth among cancer-related deaths with a low 5-year overall survival rate of less than 13%. At present, treatment of pancreatic cancer is still based on chemotherapy, but the efficacy is limited. Thus, a novel therapeutic agent for pancreatic cancer therapy is urgently needed. A library of compounds was screened, and YKL-06-061, a selective inhibitor of salt-inducible kinases (SIKs), was discovered for its ability of inhibiting the proliferation and metastasis of pancreatic cancer cells in vitro and reducing the growth of xenografts in nude mice in vivo . The results from transcriptome analysis showed that YKL-06-061 influenced the mRNA levels of many genes related to c-Myc and SIK1 signals. Based on this, it was found that YKL-06-061 induced cell cycle arrest at the G1 phase and decreased the levels of c-Myc, CDK4, and cyclin D1 protein. At the same time, YKL-06-061 inhibited invasion and metastasis of cancer cells, increased the levels of SIK1 and E-cadherin protein, and lowered vimentin and ZEB-1. Moreover, YKL-06-061 effectively enhanced the antiproliferation of gemcitabine or doxorubicin in pancreatic cancer cells in a synergistic manner. Collectively, these findings implicate YKL-06-061 as a promising therapeutic agent for patients with pancreatic cancer., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Tanshinones are a group of compounds in Salvia miltiorrhiza. Although the effects of tanshinone I (T1) and tanshinone IIA (T2A) are widely concerned, the mechanisms of T1 and T2A in lung cancer is rarely studied., Experimental Procedure: Xenograft tumor growth was performed to detect the role of T1/T2A in vivo. Next-generation sequencing of miRNA expression profiles in T1/T2A-treated A549 cells showed that T1/T2A upregulated the expression of the let-7 family. Then, let-7a-5p and its downstream target gene BORA were identified as the research objects in this paper. Mechanistically, we examined the interplay between miR-let-7 and BORA through the dual-luciferase reporter assay. Finally, the potential regulatory role of T1/T2A on Lin28B and MYC was explored., Results: This study found that the let-7 family was significantly up-regulated via "Next-generation" sequencing (NGS) in the T1/T2A-treated A549 cell line, while BORA was downregulated. BORA was confirmed as a direct target of let-7. LncRNA MYCLo-5 was up-regulated after treatment with tanshinones. Knockdown of MYCLo-5 promoted the cell cycle and proliferation of non-small cell lung cancer (NSCLC) cells., Conclusions: This study explored the effects of tanshinone T1 and T2A on NSCLC in vitro and in vivo, revealing the T1/T2A-let-7/BORA/MYCLo-5 regulatory pathway, which provided new insights for lung cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The integrated analysis of histone modifier enzymes in solid tumors, especially in esophageal squamous cell carcinoma (ESCC), is still inadequate. Here, we investigate the expression levels of histone modifier enzymes in ESCC tissues. Notably, KAT8 (lysine acetyltransferase 8) is identified as a prognostic and therapeutic biomarker in ESCC. Esophageal-tissue-specific deletion of KAT8 in mice led to less tumor burden after induction of tumorigenesis via 4-nitroquinoline N-oxide (4NQO) treatment compared with wild-type mice. Meanwhile, silencing KAT8 significantly suppresses tumor growth in cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Mechanically, we confirm that KAT8 regulates c-Myc protein stability by directly binding it. Furthermore, we design and screen a specific KAT8 inhibitor (CHI-KAT8i5) that significantly attenuates tumor growth in vitro and in vivo, providing promising potential for clinical application. Thus, our work identifies that KAT8 could serve as a potential clinically relevant biomarker and therapeutic target in patients with ESCC and that KAT8 inhibitor is a promising lead candidate for ESCC therapy., Competing Interests: Declaration of interests We have a patent application related to this work (patent number: 202210601619.2)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression of SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm the existence of disulfidptosis in pancreatic ductal adenocarcinoma (PDAC) and elucidate the role of Cancer Susceptibility 8 (CASC8) in this process., Methods: The existence of disulfidptosis in PDAC was assessed using flow cytometry and F-actin staining. CASC8 expression and its clinical correlations were analyzed using data from The Cancer Genome Atlas (TCGA) and further verified by chromogenic in situ hybridization assay in PDAC tissues. Cells with CASC8 knockdown and overexpression were subjected to cell viability, EdU, transwell assays, and used to establish subcutaneous and orthotopic tumor models. Disulfidptosis was detected by flow cytometry and immunofluorescence assays. RNA sequencing and metabolomics analysis were performed to determine the metabolic pathways which were significantly affected after CASC8 knockdown. We detected the glucose consumption and the NADP + /NADPH ratio to investigate alterations in metabolic profiles. RNA immunoprecipitation combined with fluorescence in situ hybridization assay was used to identify protein-RNA interactions. Protein stability, western blotting and quantitative real-time PCR assays were performed to reveal potential molecular mechanism., Results: Disulfidptosis was observed in PDAC and could be significantly rescued by disulfidptosis inhibitors. CASC8 expression was higher in PDAC samples compared to normal pancreatic tissue. High CASC8 expression correlated with a poor prognosis for patients with PDAC and contributed to cancer progression in vitro and in vivo. Furthermore, CASC8 was associated with disulfidptosis resistance under glucose starvation conditions in PDAC. Mechanistically, CASC8 interacted with c-Myc to enhance the stability of c-Myc protein, leading to the activation of the pentose phosphate pathway, a reduction of the NADP + /NADPH ratio and ultimately inhibiting disulfidptosis under glucose starvation conditions., Conclusions: This study provides evidence for the existence of disulfidptosis in PDAC and reveals the upregulation of CASC8 in this malignancy. Furthermore, we demonstrate that CASC8 acts as a crucial regulator of the pentose phosphate pathway and disulfidptosis, thereby promoting PDAC progression., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures related to patients were carried out in accordance with International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS). Consent for publication: All authors had agreed to publish this manuscript. Competing interests: The authors have declared that no conflict of interest exists., (© 2025. The Author(s).)

The master regulator transcription factor MYC is implicated in numerous human cancers, and its targeting is a long-standing challenge in drug development. MYC is a typical 'undruggable' target, with no binding pockets on its DNA binding domain and extensive intrinsically disordered regions. Rather than trying to target MYC directly with classical modalities, here we engineer synthetic miniproteins that can bind to MYC's target DNA, the enhancer box (E-Box), and potently inhibit MYC-driven transcription. We crafted the miniproteins via structure-based design and a combination of solid phase peptide synthesis and site-specific crosslinking. Our lead variant, DuoMYC, binds to E-Box DNA with high affinity (K D ~0.1 μM) and is able to enter cells and inhibit MYC-driven transcription with submicromolar potency (IC 50 =464 nM) as shown by reporter gene assay and confirmed by RNA sequencing. Notably, DuoMYC surpasses the efficacy of several other recently developed MYC inhibitors. Our results highlight the potential of engineered synthetic protein therapeutics for addressing challenging intracellular targets., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Phosphodiesterase-5 (PDE5) inhibitors have shown promise as anti-cancer agents in malignancies. However, their specific effects on gastric cancer (GC) and the underlying mechanisms remain elusive. Our aim was to investigate this by combining evidence from population-based studies with data obtained from in vivo and in vitro experiments. By combing a couple of nationwide Swedish registers, GC patients who received PDE5 inhibitors were compared to matched controls while adjusting for confounding factors. The anti-tumor effect and mechanism of the PDE5 inhibitor sildenafil were evaluated via using tumor cells, patient-derived tumor organoids and xenograft animal models in GC. A total of 161 Swedish GC patients from a nationwide population-based cohort who received post-diagnostic PDE5 inhibitors demonstrated lower cancer-specific mortality compared to the controls (HR = 0.66, 95% CI = 0.47-0.92, P = 0.016). Functionally, the PDE5 inhibitor sildenafil exhibited the suppressive ability to prevent oncogenic growth in GC. Mechanistically, sildenafil restrained GC growth by directly activating PKG through PDE5 inhibition for regulating c-MYC expression via its phosphorylation and ubiquitination degradation, thereby suppressing c-MYC stability for IL-6 transcription within the downstream IL-6/JAK/STAT3 signalling pathway. The PDE5 inhibitor sildenafil may serve as a promising adjuvant for GC therapy if further randomized clinical trials confirm its efficacy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Abdominal wall endometriosis (AWE) is a clinical disorder with unknown pathogenesis with an incidence between 0.03% and 1% in women affected by cutaneous/scar endometriosis. We investigated the pathological, molecular cytogenetic and cell proliferation features of a primary AWE developed in rectus abdominis muscle in a patient without co-existing pelvic endometriosis. An investigational model of cultured stromal cells was additionally established. Histologically, the lesion revealed areas of endometrial-like glands surrounded by a thick stromal layer in addition to numerous disseminated foci composed exclusively of stromal cells. Beyond the strong expression of Estrogen (ER) and Progesterone receptors (PRs), consistent immunolabeling for several mesenchymal stromal/stem cell antigens and oncoproteins was revealed in both the endometrioma as well as in the cultured stromal cells. The Fluorescence in situ hybridization (FISH) analysis of the endometrioma demonstrated a structural alteration of the c-MYC protooncogene, with a mean of three gene copies in 3% to 5% of both glandular and stromal cells. The FISH assay applied on the cultured cells showed c-MYC gene amplification, with an average number of more than six gene copies in 18% to 25% of the cellular nuclei. Altogether, these results markedly highlight the pathological and molecular features of idiopathic AWE essential for histo-pathogenetic categorization.

Basic helix-loop-helix domains in yeast regulatory proteins Ino2 and Ino4 mediate formation of a heterodimer which binds to and activates expression of phospholipid biosynthetic genes. The human proto-oncoprotein c-Myc (Myc) and its binding partner Max activate genes important for cellular proliferation and contain functional domains structure and position of which strongly resembles Ino2 and Ino4. Since Ino2-Myc and Ino4-Max may be considered as orthologs we performed functional comparisons in yeast. We demonstrate that Myc and Max could be stably synthesized in S. cerevisiae and together significantly activated a target gene of Ino2/Ino4 but nevertheless were unable to functionally complement an ino2 ino4 double mutant. We also map two efficient transcriptional activation domains in the N-terminus of Myc (TAD1: aa 1-41 and TAD2: aa 91-140), corresponding to TAD positions in Ino2. We finally show that coactivators such as TFIID subunits Taf1, Taf4, Taf6, Taf10 and Taf12 as well as ATPase subunits of chromatin remodelling complexes Swi2, Sth1 and Ino80 previously shown to interact with TADs of Ino2 were also able to bind TADs of Myc, supporting the view that heterodimers Ino2/Ino4 and Myc/Max are evolutionary related but have undergone transcriptional rewiring of target genes., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests. Ethics approval: Not applicable (no studies with human participants or animals were performed in this study). Consent to participate: Not applicable. Consent for publication: All authors have read and approved the final manuscript., (© 2025. The Author(s).)

Colorectal cancer (CRC) remains a major global health challenge, with high rates of incidence and mortality. This study investigates the role of protein arginine methyltransferase 6 (PRMT6) as an oncogene in CRC and its mechanistic involvement in tumor progression. We found that PRMT6 is significantly overexpressed in CRC tissues compared to adjacent normal tissues and is associated with poorer patient survival. Functional assays demonstrated that PRMT6 promotes CRC cell proliferation, migration, and invasion. Mechanistically, PRMT6 enhances MYC signaling by stabilizing c-MYC through mono-methylation at arginine 371, which inhibits c-MYC poly-ubiquitination and subsequent degradation. This post-translational modification is crucial for PRMT6-induced cancer cell proliferation. Xenograft models further validated that PRMT6 knockdown results in reduced tumor growth and decreased c-MYC levels. Our findings highlight PRMT6 as a key regulator of c-MYC stability and CRC progression, suggesting that targeting PRMT6 or its effects on c-MYC could offer a promising strategy for CRC treatment., Competing Interests: Declarations. Ethical approval and consent to participate: The current study was approved by the Ethical Review Committee of Shandong University (No.KYLL-2021(ZM)-209). All patients who participated in the current study provided signed informed consent. Consent for publication: All authors approved the final manuscript draft for publication. Competing interests: Authors declared no conflict of interest., (© 2025. The Author(s).)

Glutamine metabolism is essential for infectious spleen and kidney necrosis virus (ISKNV) replication. Glutaminase 1 (GLS1), the key enzyme of the glutamine metabolism, and c-Myc positively regulate ISKNV infection, while c-Myc is closely correlated with GLS1. However, the regulatory mechanism among ISKNV, c-Myc and glutamine metabolism remains unclear. Here, we indicated that c-Myc increased glutamine uptake by increasing the GLS1, glutamate dehydrogenase (GDH) and isocitrate dehydrogenase (IDH2) expression of glutamine metabolism. ISKNV ORF102R, ORF093R and ORF118L co-located with c-Myc in CPB cells. Co-IP results showed that ISKNV ORF102R and ORF093R interacted with c-Myc, while ORF118L did not interact with c-Myc. The expression levels of c-Myc, GLS1 and IDH2 were increased in ISKNV ORF093R expression cells, and the mRNA and protein levels of GLS1 were upregulated in ISKNV 102R-expressing cells. These results indicated that ISKNV reconstructed glutamine metabolism to satisfy the energy and macromolecule requirements for virus proliferation by ORF093R and ORF102R interacting with c-Myc, which provides the foundation for innovative antiviral strategies.

The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of different cell populations displaying distinctive genetic and transcriptomic profiles. GBM with primitive neuronal component (PNC), recently identified by DNA methylation-based classification as a peculiar GBM subtype (GBM-PNC), is a poorly recognized and aggressive GBM variant characterised by nodules containing cells with primitive neuronal differentiation along with conventional GBM areas. In addition, the presence of a PNC component has been also reported in IDH-mutant high-grade gliomas (HGGs), and to a lesser extent to other HGGs, suggesting that regardless from being IDH-mutant or IDH-wildtype, peculiar genetic and/or epigenetic events may contribute to the phenotypic skewing with the emergence of the PNC phenotype. However, a clear hypothesis on the mechanisms responsible for this phenotypic skewing is still lacking. We assumed that the biphasic nature of these entities represents a unique model to investigate the relationships between genetic alterations and their phenotypic manifestations. In this study we show that in HGGs with PNC features both components are highly enriched in genetic alterations directly causing cell cycle deregulation (RB inactivation or CDK4 amplification) and p53 pathway inactivation (TP53 mutations or MDM2/4 amplification). However, the PNC component displays further upregulation of transcriptional pathways associated with proliferative activity, including overexpression of MYC target genes. Notably, the PNC phenotype relies on the expression of EBF3, an early neurogenic transcription factor, which is directly controlled by MYC transcription factors in accessible chromatin sites. Overall our findings indicate that the concomitant presence of genetic alterations, impinging on both cell cycle and p53 pathway control, strongly predisposes GBM to develop a concomitant poorly differentiated primitive phenotype depending on MYC-driven EBF3 transcription in a subset of glioma stem-like progenitor cells., Competing Interests: Declarations. Conflict of interest: The authors declare that there are no competing interests. Ethics approval and consent to participate: All methods and experimental protocols related to human subjects were approved and carried out in compliance with the Declaration of Helsinki and with policies approved by the Institutional Review Board of Ethics Committee of Spedali Civili of Brescia. Surgical cases of human gliomas were part of the archival material obtained for diagnostic purposes from the Pathology Unit at Spedali Civili of Brescia, University of Brescia. Specifically, for retrospective and exclusively observational studies on archival material obtained for diagnostic purposes, patient consent was not needed (Delibera del Garante n. 52 del 24/7/2008 and DL 193/2003). Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Osteoarthritis (OA), affecting > 500 million people worldwide, profoundly affects the quality of life and ability to work. The mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in OA. To address the lack of studies focused on synovial cells in OA, we evaluated the expression patterns and roles of the MAPK signaling pathway components in OA synovial tissues using bioinformatics. The JUN, MYC, and VEGFA expression levels were significantly higher in the synovial tissues of patients with OA than in control tissues. These loci were closely related to abnormal proliferation, inflammation, and angiogenesis in the synovial tissues of patients with OA. We speculate that Myc and VEGFA activate the p38-MAPK signaling pathway to further activate Jun, thereby promoting abnormal inflammation, proliferation, and angiogenesis in OA synovial tissue. The high MYC, JUN, and VEGFA expression was positively correlated with the patients' K-L score, pain time, and synovial score. Furthermore, the high p38-MAPK and P-p38-MAPK expression confirmed that the abnormal expression and activation of the MAPK signaling pathway occurred in the synovial tissue of patients with OA. Our findings may provide a new direction for the clinical diagnosis and treatment of OA and insights into its pathogenesis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: The study was conducted in accordance with the Declara-tion of Helsinki, and approved by the Ethics Committee of Anhui Medical University (S20210085 and date of approval 2021/03/31).Informed Consent Statement: Informed consent was obtained from all subjects involved in the study prior to participation., (© 2025. The Author(s).)

Hepatocellular carcinoma (HCC) is a common cancer characterized by robustly proliferative and metastatic capabilities. Bromodomain-containing proteins are critical to the development of diverse diseases via regulating cell proliferation, differentiation, and death. However, the role of Bromodomain-containing protein 3 (BRD3) in HCC is elusive. Here, we found that BRD3 is notably upregulated in HCC samples and promotes the proliferation of HCC cells. Depletion of BRD3 notably inhibits the expression of c-MYC and Cyclin D1 and abrogates cell cycle progression in HCC cells. Co-IP and biomass spectrometry found that Ku70 interacts with BRD3 in the nucleus. The Ku70-BRD3 complex increases the expression of Cyclin D1 and c-MYC at transcriptional level in HCC. Additionally, depletion of Ku70/BRD3 ameliorates the growth of HCC xenografts established in mice. More importantly, the expression of Ku70 or BRD3 is positively correlated with the protein expression of c-MYC and Cyclin D1 in HCC samples. High expression of BRD3 or Ku70 is closely associated with poor prognosis in HCC patients. Overall, we reveal the important role of the Ku70-BRD3 complex in the onset and progression of HCC, suggesting that the Ku70-BRD3 complex is a promising target for clinical intervention in HCC., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes. How MZB cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. We found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulated MZB cell pool size, migration, and function. Dll1 could not be replaced by the alternative Notch ligand Dll4. Dll1-Notch2 signaling regulated a Myc-dependent gene expression program fostering cell growth and a Myc-independent program controlling cell-movement regulators such as sphingosine-1 phosphate receptor 1 (S1PR1). S1pr1-deficient B cells experienced Notch signaling within B cell follicles without entering the MZ and were retained in the spleen upon Notch deprivation. Key elements of the mouse B cell Notch regulome were preserved in subsets of human memory B cells and B cell lymphomas. Thus, specialized niches program the poised state and patrolling behavior of MZB cells via conserved Myc-dependent and Myc-independent Notch2-regulated mechanisms., Competing Interests: Declaration of interests S.K. is currently employed by Century Therapeutics; L.C. by Interius BioTherapeutics; D.G.A. by Aro Biotherapeutics; and C.W.S by Gilead Sciences. L.M. is a current and C.W.S. a former employee of Genentech. I.M. has received research funding from Genentech and Regeneron and is a member of Garuda Therapeutics’s scientific advisory board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: The theory of traditional Chinese medicine (TCM) views leukemia as an imbalance between cell growth and death mainly caused by blood stasis. Medicinal plants Aglaia Lour. (family Meliaceae) are traditionally used as folk medicine in China. It possesses the effects of removing blood stasis and swelling for treatment of cancer. Rocaglamide (RocA) is the main active phytochemical component of the genus Aglaia Lour. Possessing highly anti-leukemia properties. However, the molecular mechanisms by which RocA exerts its anti-growth effect on erythroleukemia cells are largely unknown., Aim of the Study: This study aimed to explore the underlying mechanism and glucose metabolism regulation effects of RocA responsible for its anti-erythroleukemia activity., Materials and Methods: Human erythroleukemic cells were tested for glucose metabolism and treated with glucose deprivation and RocA. MTT assay, cell cycle and apoptosis were used to elucidate growth inhibition. Glucose uptake, glucose consumption and lactate production were evaluated for identification of glucose metabolism. Luciferase assay and ChIP were used to examine the transcriptional activity of c-MYC on the conserved E-boxes binding of the TXNIP (thioredoxin-interacting protein) and HK2 (hexokinase 2) genes. siRNA, shRNA and exogenous transfection were employed to elucidate the effects of TXNIP and HK2 on glucose metabolism., Results: We find that glucose deprivation results in growth inhibition, cell cycle arrest and extensive apoptosis in erythroleukemic cells accompanied by downregulation of c-MYC and HK2, responsible for glucose metabolism. The similar results emerged in RocA treated erythroleukemic cells in presence of glucose. RocA is shown to decrease glucose uptake, glucose consumption and lactate production. Mechanistically, RocA dramatically increases TXNIP expression through interference with c-MYC binding to the promoter of the TXNIP gene. RocA also represses c-MYC transcriptional recognition of conserved E-boxes in the HK2 first intron, resulting in HK2 loss. These results implicate c-MYC as an important regulator of TXNIP and HK2 after RocA treatment. TXNIP overexpression or knockdown of HK2 suppresses the proliferation of erythroleukemic cells. Ectopic TXNIP expression restricts glucose uptake and HK2 suppression decreases glucose utilization. Further, our data suggests that loss of HK2 weakens the RocA-driven inhibition effects. We propose repression of c-MYC or the binding by RocA upregulates TXNIP and downregulates HK2, possibly contributes to growth inhibition in human erythroleukemic cells., Conclusions: This study uncovers molecular mechanism of RocA against leukemic cells proliferation, linking the anti-erythroleukemia properties of RocA to glucose metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Group 3 medulloblastoma (MBGRP3) represents around 25% of medulloblastomas and is strongly associated with c-MYC (MYC) amplification, which confers significantly worse patient survival. Although elevated MYC expression is a significant molecular feature in MBGRP3, direct targeting of MYC remains elusive, and alternative strategies are needed. The metabolic landscape of MYC-driven MBGRP3 is largely unexplored and may offer novel opportunities for therapies., Methods: To study MYC-induced metabolic alterations in MBGRP3, we depleted MYC in isogenic cell-based model systems, followed by 1H high-resolution magic-angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics, to assess changes in intracellular metabolites and pathway dynamics., Results: Steady-state metabolic profiling revealed consistent MYC-dependent alterations in metabolites involved in one-carbon metabolism such as glycine. 13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC knockdown, which coincided with lower expression and activity of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in this pathway. Furthermore, MYC-overexpressing MBGRP3 cells were more vulnerable to pharmacological inhibition of PHGDH compared to those with low expression. Using in vivo tumor-bearing genetically engineered and xenograft mouse models, pharmacological inhibition of PHGDH increased survival, implicating the de novo serine/glycine synthesis pathway as a pro-survival mechanism sustaining tumor progression. Critically, in primary human medulloblastomas, increased PHGDH expression correlated strongly with both MYC amplification and poorer clinical outcomes., Conclusions: Our findings support a MYC-induced dependency on the serine/glycine pathway in MBGRP3 that represents a novel therapeutic treatment strategy for this poor prognosis disease group., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management., Methods: We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases., Results: Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a "canonical" very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS., Conclusions: MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

MEK inhibitors, such as trametinib, have shown therapeutic potential in head and neck squamous cell carcinoma (HNSCC). However, the factors influencing cancer cell sensitivity and resistance to MEK inhibition remain poorly understood. In our study, we observed that MEK inhibition significantly reduced the expression of MYC, a transcription factor critical for the therapeutic response. MYC overexpression markedly enhanced the sensitivity of HNSCC cells to trametinib, as evidenced by delayed wound healing and reduced colony formation. Cell cycle analysis revealed that trametinib induced a G1 phase arrest, whereas MYC overexpression accelerated cell cycle progression, with a reduced induction of p27 and p21 and diminished decreases in E2F1 and phospho-Ser2/5 levels. Flow cytometry and protein analyses demonstrated that MYC overexpression amplified trametinib-induced apoptosis and DNA damage, as evidenced by elevated levels of pro-apoptotic markers (p53, cleaved PARP, and BIM) and γH2AX. In vivo xenograft models confirmed these findings, showing increased sensitivity to trametinib in MYC-overexpressing tumors. Moreover, MEK inhibition increased autophagy in HNSCC cells, a factor critical for therapeutic resistance. Inhibiting trametinib-induced autophagy further enhanced apoptotic cell death. These findings suggest that MYC expression and autophagy play crucial roles in HNSCC's response to MEK inhibition. Combining trametinib with autophagy inhibition may improve therapeutic outcomes in HNSCC.

Background: The Arp2/3 complex is a key regulator of tumor metastasis, and targeting its subunits offers potential for anti-metastatic therapy. However, the expression profiles, prognostic relevance, and diagnostic value of its subunits across cancers remain poorly understood. This study aims to investigate the clinical relevance of Arp2/3 complex subunits, particularly ARPC1A, in pan-cancer, and to further analyze the potential biological mechanisms of ARPC1A, as well as its association with immune infiltration and chemotherapy drug sensitivity., Methods: To explore the differential expression of Arp2/3 complex subunits and their clinical relevance across cancers, we analyzed data from TCGA and GTEx databases. The relationship between ARPC1A and immune infiltration, as well as its interactions with functional proteins, was examined using the TCPA and TIMER2.0 databases. Gene Set Enrichment Analysis (GSEA) was performed to identify ARPC1A-associated signaling pathways. Chemotherapy drug sensitivity correlated with ARPC1A expression was assessed using CellMiner, GDSC, and CTRP databases. The effect of ARPC1A on c-Myc expression was validated by quantitative PCR (qPCR) and Western blot. Finally, the biological role of ARPC1A in non-small cell lung cancer (NSCLC) cells was further validated using CCK-8, EdU incorporation, colony formation, and Transwell assays., Results: The Arp2/3 complex subunits, particularly ARPC1A, are frequently overexpressed in a majority of cancers, correlating with poor prognostic outcomes and demonstrating significant diagnostic utility. Copy number variations may play a role in the dysregulation of Arp2/3 complex subunit expression. The small molecule X4.5.dianilinophthalimide has shown promise as a targeted therapeutic agent in a pan-cancer context. Functional predictions indicate that ARPC1A is implicated in oxidative phosphorylation pathways and cell proliferation-related signaling pathways, including those mediated by MYC, with ASNS potentially acting as an upstream regulator. Furthermore, ARPC1A has been implicated in the resistance to chemotherapy drugs, including gefitinib. In vitro experiments corroborate that ARPC1A may enhance malignant phenotypes in non-small cell lung cancer (NSCLC) cells through the regulation of c-Myc expression., Conclusion: Our study offers novel insights into targeting Arp2/3 complex subunits as an anti-cancer strategy and underscores the potential of ARPC1A as a novel biomarker for tumor diagnosis, prognosis, and the prediction of immune therapy responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Zhou, Chen, Chen, Hu, Wang and Wang.)

ATPase family AAA domain-containing protein 2 (ATAD2) is significantly up-regulated in many cancer types and contributes to poor patient outcomes. ATAD2 exhibits a multidomain architecture comprising an N-terminal acidic domain, two AAA+ ATPase domains, a bromodomain, and a C-terminal domain. The AAA+ ATPase domain facilitates protein oligomerization and ATP binding, while the bromodomain recognizes acetylated lysine in histones and nonhistone proteins. ATAD2 involvement in cancer extends across multiple signaling pathways, such as Rb-E2F1, PI3K/AKT, and TGF-β1/Smad3, which promotes cell proliferation and cancer progression. Herein, we report that ATAD2 directly interacts with TWIST1, and both N-terminal regions of proteins mediate the interaction. Immunofluorescence experiments suggested that ATAD2 and TWIST1 primarily colocalize in the nucleus. Notably, our qPCR results revealed the functional significance of ATAD2-TWIST1 interaction by demonstrating their synergistic effect on the transcriptional activation of MYC in colorectal carcinoma cell lines. Moreover, the ChIP-qPCR result further indicates that ATAD2 and TWIST1 significantly localize in the promoter of the MYC gene. In addition, analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) data suggests a correlation between ATAD2, TWIST1, and MYC overexpression and poor survival rates in colorectal carcinoma. Lastly, the overexpression of ATAD2 and TWIST1 enhances cell proliferation, emphasizing their role in colorectal carcinoma progression through MYC activation. Together, these results suggest that ATAD2 is a crucial factor in TWIST1-dependent MYC gene activation, resulting in an active ATAD2-TWIST1-MYC axis that contributes to colon cancer cell proliferation.

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2 . The expression of stemness genes SOX2 , NES , and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53 . Among the genes regulated by VPA, the stemness regulators MYC and NES showed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression of MYC and an increase in TP53 .

The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of D347-2761, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound A1 displayed IC 50 values of 6.32 μM and 11.39 μM against the A549 and NCI-H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC 50 values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

Roles of liver-specific genes (LSGs) in tumor initiation and progression are rarely explored in hepatocellular carcinoma (HCC). Here we show that LSGs are generally downregulated in HCC tumor tissues compared to non-HCC liver tissues, and low-LSG HCCs show poor prognosis and the activated c-Myc pathway. Among the c-Myc- and patient prognosis-associated LSGs, PGRMC1 significantly blocks c-Myc-induced orthotopic HCC formation. The role of PGRMC1 depends on its localization to the endoplasmic reticulum (ER) membrane, where PGRMC1 interacts with PERK through their ER luminal domains. This interaction in turn activates PERK in an ER stress-independent manner, which phosphorylates eIF2α and consequently inhibits c-Myc protein translation. In HCC patients, PGRMC1 level is significantly reduced in tumor tissues and negatively associated with the c-Myc signature. Patients with low-PGRMC1 in their tumors have poor prognosis. Collectively, deregulated LSGs in HCC are associated with the c-Myc pathway activation and PGRMC1 blocks c-Myc-induced hepatic carcinogenesis through promoting ER stress-independent PERK activation., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we have performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice have exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 has been deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency has resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion has also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD has been found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells have stimulated Interferon-γ-dependent epithelial regeneration in co-cultured organoids, and Interferon-γ has directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration., Competing Interests: Competing interests: The authors declare no competing financial interests. A.M.H. and C.A.L hold intellectual property related to Interleukin-22, and A.M.H. has a collaboration with Evive Biotechnology (Shanghai) Ltd, which supported a multicenter clinical trial studying use of Interleukin-22 in patients with GVHD. A.M.H. also serves in a volunteer capacity as a member of the Board of Directors of the American Society for Transplantation and Cellular Therapy (ASTCT)., (© 2024. The Author(s).)

Breast cancer is the second leading cause of death in women globally, and it remains a health burden due to poor therapy response, cancer cell drug resistance, and the debilitating side effects associated with most therapies. One approach to addressing the need to improve breast cancer therapies has been to elucidate the mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. The T-box transcription factor, TBX3, is upregulated in breast cancer, in which it contributes to important oncogenic processes, and it has been validated as a potential therapeutic target. Here, we investigated the molecular mechanisms that upregulate TBX3 in breast cancer, and we show that it involves transcriptional activation by c-Myc, post-translational modification by AKT1 and AKT3, and interaction with the molecular chaperone Hsc70. Together, the results from this study provide evidence that c-Myc, AKT, Hsc70, and TBX3 form part of an important oncogenic pathway in breast cancer and thus reveal versatile ways of interfering with the oncogenic activity of TBX3 for the treatment of this neoplasm. Implications: Targeting the c-Myc/AKT/TBX3/Hsc70 signaling axis may be an effective treatment strategy for TBX3-driven breast cancer., (©2024 American Association for Cancer Research.)

CAR-T cells and monoclonal antibodies (mAbs) are immunotherapeutics that have shown efficacies against certain malignancies. However, their broad application is hindered by the scarcity of tumor-associated antigens on tumor cell surfaces. Previous investigations unveiled the unique capacity of pH-low insertion peptide (pHLIP) to anchor to plasma membranes under acidic conditions. Considering that an acidic tumor microenvironment is a hallmark of solid tumors, we engineered a novel peptide, Myc-pHLIP, by tethering a surrogate epitope tag, the c-Myc-tag, to pHLIP. We evaluated the efficiency of Myc-pHLIP in inserting the artificial c-Myc-tag onto the plasma membrane of malignant cells and determined if this engraftment could convert it into a therapeutic target for CAR-T cells or mAbs. Our in vitro experiments demonstrated that incubating Myc-pHLIP with tumor cells in acidic media triggered significant killing by either Myc-targeted CAR-T cells (Myc-CAR-T), or by an anti-Myc mAb in the presence of NK cells. In vivo studies demonstrated substantial antitumor effects with sequential administration of Myc-pHLIP followed by either Myc-CAR-T or Myc-mAb. These findings establish that Myc-pHLIP has the potential to act as a universal surrogate tumor antigen capable of directing CAR-T cells or mAbs to treat any solid tumors by concurrently targeting both malignant and stromal cells., Competing Interests: Declaration of competing interest Tomahawk Oncology Inc. has licensed an oncolytic HSV-2 developed by SXZ and XF for clinical development and commercialization, which is not directly linked to the studies in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Breast cancer (BC) is characterized by an increasing incidence and mortality rate. Juzaowan inhibits various malignant processes, although its mechanism in BC remains unclear., Methods: To evaluate the impact of Juzaowan on biological functions of BC cells, cellular assays were done to assess proliferation, migration, invasion, and apoptosis. Bioinformatics was used to identify signaling pathways affected by active ingredients of Juzaowan. BC cells were treated with Juzaowan. Western blot assayed lactate production, glucose consumption, and expression of proteins related to glycolytic pathway and STAT3/C-Myc axis., Results: Juzaowan suppressed BC cell proliferation and increased apoptosis. It downregulated anti-apoptotic protein BCL2 while upregulating pro-apoptotic proteins Bax and cleaved caspase 3. Juzaowan significantly inhibited BC cell migration and invasion. Significant upregulation of E-cadherin and significant downregulation of E-cadherin-binding protein ZEB1, N-cadherin, and vimentin were observed. Bioinformatics analysis and cellular experiments confirmed inhibition of Juzaowan on BC cell glucose uptake and glycolytic pathways-related key metabolic enzymes (GLUT1, PKM2, LDH) expressions. Western blot revealed that Juzaowan induced metabolic alterations in BC cells by impeding STAT3/C-Myc axis., Conclusion: This study elucidated molecular mechanisms of Juzaowan inhibiting BC cell glycolysis by repressing STAT3/C-Myc axis, thus suppressing malignant progression. These findings supported clinical applications of Juzaowan.

The peptides encoded by long noncoding RNAs (lncRNAs) have been shown to participate in cancer pathogenesis. In this study, lncRNA LINC00944 was validated to encode an endogenous 102-amino acid (aa) small peptide (named LINC00944 peptide). Functionally, LINC00944 peptide exerted an anti-growth effect in melanoma cells in vitro. Mechanistically, LINC00944 peptide interacted with the E1A binding protein p400 (EP400)/c-MYC complex. LINC00944 peptide also inhibited c-MYC protein expression. Furthermore, LINC00944 peptide repressed the transcriptional activity of MYC by reducing the EP400-MYC interaction, thereby reducing the levels of fatty acid metabolism- and glucose metabolism-related proteins. Our findings uncovered that LINC00944 peptide might be a promising adjuvant therapeutic agent for melanoma. Implications: This study provided the first evidence that LINC00944-encoded peptide played a critical role in the growth of melanoma cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Though Capsaicin from chili peppers was known to have antitumor effects in several cancers, the underlying antitumor pathogenesis of Capsaicin is not clear to date. Thus, the antitumor mechanism of Capsaicin was explored in Hep3B and Huh7 hepatocellular carcinoma (HCC) cells in relation to c-Myc/monocarboxylate transporter 4 (MCT4) signaling. To elucidate the antitumor mechanism of capsaicin, cytotoxicity assay, cell cycle analysis, Western blotting, RT-qPCR, RNA interference, ELISA, immunoprecipitation, and mouse xenograft model were used in this work. Capsaicin increased the cytotoxicity, subG1 population, and the number of TUNEL-positive bodies in Huh7 and Hep3B cells. Consistently, Capsaicin diminished the expression of pro-PARP, HK2, PKM2, LDHA, glucose transporter type 1 (Glut1), c-Myc, and monocarboxylate transporter 4 (MCT4) in Huh7 and Hep3B cells, along with decreased production of glucose, lactate, and ATP. However, a glycolysis end product pyruvate treatment reversed the capacity of Capsaicin to attenuate the expression of pro-PARP, HK2, c-Myc, and MCT4 in Hep3B cells. Furthermore, Capsaicin reduced c-Myc stability in the presence of cycloheximide and induced c-Myc ubiquitination in Hep3B cells, while c-Myc directly binds to MCT4 as a lactate transporter and downstream of c-Myc in Hep3B cells by immunoprecipitation and correlation factor (Spearman efficient = 0.0027). Furthermore, a preliminary analysis of an animal study reveals that Capsaicin significantly suppressed the growth of Hep3B cells inoculated in BALB/c nude mice without hurting body weight, liver, and spleen. Our findings provide novel evidence that Capsaicin exerts apoptotic and anti-Warburg effect via c-Myc/MCT4 signaling axis as a potent anticancer candidate for liver cancer therapy., (© 2024 John Wiley & Sons Ltd.)

Double-hit lymphoma (DHL) is a high-risk subtype of large B-cell lymphoma, defined by concurrent rearrangements MYC and BCL2 . The diagnosis is confirmed through histologic and immunophenotypic examination and fluorescence in situ hybridization (FISH) to demonstrate the rearrangements. DHL morphology ranges from DLBCL to high-grade B-cell lymphoma which can resemble Burkitt lymphoma and is almost always germinal center B-cell like (GCB). Prognosis is influenced by elevated lactate dehydrogenase (LDH), advanced stage, and extranodal involvement, among other factors. Treatment outcomes vary, but intensive chemotherapy regimens such as dose-adjusted EPOCH-R have shown the most promising results, though low-risk cases do occur and may do well with less intensive treatments. Recent therapeutic advances such as CAR-T cells and bispecific antibodies offer promise for patients with relapsed/refractory disease. This review synthesizes data from recent literature to provide a comprehensive analysis of the molecular underpinnings, diagnostic criteria, prognostic factors, and therapeutic strategies for DHL.

Breast cancer progression and metastasis are closely connected to changes in glucose and glutamine metabolism. While Novel (nua) kinase family 1 (NUAK1) and Novel (nua) kinase family 2 (NUAK2), which are two members of the AMPK-related kinases, have been associated with breast tumorigenesis, their role in the metabolic reprogramming that occurs during breast cancer progression remains unclear. Our research uncovers that NUAKs expression is significantly higher in breast cancer tissues and cell lines, and it is positively related to glycolysis, the pentose phosphate pathway (PPP), glutamine metabolism, and a poor prognosis for breast cancer patients. We show that NUAKs significantly increase metabolic reprogramming, including aerobic glycolysis, PPP, and glutamine metabolism in triple negative breast cancer subtypes but only induce aerobic glycolysis and PPP in luminal breast cancer subtypes to meet the anabolic demands of rapidly dividing breast cancer cells. In contrast, the depletion of NUAKs has the opposite effect. Mechanistic insights reveal that NUAKs activate mammalian target of rapamycin (mTOR) signaling, which in turn upregulates the c-Myc transcription factor, a crucial regulator of glucose and glutamine metabolic gene expression. Moreover, we demonstrate that NUAKs enhance mTOR/c-Myc signaling pathways, leading to increased glucose and glutamine reprogramming, which supports rapid cell proliferation and metastatic potential in breast cancer cells. Importantly, pretreating breast cancer cells with mTOR inhibitors blocked the metabolic reprogramming and tumor-promoting effect of NUAK1/2. Therefore, targeting NUAKs may represent a novel therapeutic strategy for the treatment of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Double expression (DE) is a World Health Organization-recognized adverse prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, the prognostic value of DE in the genetic subtyping era and potential mechanisms remain to be explored. We enrolled 246 DLBCL patients diagnosed between December 2021 and September 2023 in a Jiangsu Province Hospital cohort and included 930 DLBCL patients from three published studies in an external cohort. Double-expression DLBCL (DEL) in the external cohort was mainly distributed in the OTHER subtype (42.0%), EZB subtype (28.3%), and MCD subtype (15.0%), whereas the MCD subtype exhibited the highest ratio of DEL. DEL was significantly related to unfavorable overall survival (OS) and progression-free survival (PFS) in DLBCL, but only in EZB and OTHER subtypes that DEL retained remarkably adverse impacts on survivals compared to non-DEL. We explored the prognostic value of clinical and genetic parameters in DEL patients and found only ST2 showed better OS than A53 in DEL patients, whereas the other subtypes showed no significant difference. DEL showed similarities with the MCD subtype in mutation profiles. Furthermore, RNA-sequencing analyses exhibited upregulation in tumor proliferation-related pathways in DEL patients, but downregulation in extracellular matrix organization, T-cell activation and proliferation, type II interferon production, and pathways associated with cell death might contribute to the poor outcomes of DEL patients., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The transcription factor MYC has long been recognized for its pivotal role in transcriptional regulation of genes fundamental for cellular processes such as cell cycle, apoptosis, and metabolism. Dysregulation of MYC activity is implicated in various diseases, most notably cancer, where MYC drives uncontrolled cell proliferation and growth. Despite its significant role in cancer biology, targeting MYC for therapeutic purposes has been challenging due to its highly disordered protein structure. Hence, recent research efforts have focused on identifying the transcriptional mechanisms underlying MYC function to identify alternative strategies for intervention. This review summarizes recent advances in our understanding of how MYC orchestrates context-dependent and -independent gene-regulatory activities in cancer. Based on recent insights into the gene-regulatory function of MYC at enhancers, we propose an extension of the gene-specific affinity model. In this revised model, MYC enhancer activity drives context-specific gene programs that are distinct from the ubiquitously activated set of core MYC target genes driven by MYC promoter binding. The increased MYC enhancer activity in cancer and the distinct function of MYC at these regions compared to promoters may provide an opportunity for designing therapeutic approaches selectively targeting MYC enhancer activity in cancer cells., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc-Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)