关键词： ATF3   biomarkers   chemoimmunotherapy   IFN signaling pathway   NSCLC   pathological response  

摘要： BackgroundNeoadjuvant chemoimmunotherapy has achieved high downstaging and pathologic response rates in nonsmall-cell lung cancer (NSCLC), but outcomes vary significantly. Early identification of beneficiaries remains a *** study analyzed baseline transcriptomic data from 24 NSCLC patients (9 major pathological response [MPR], 15 nonmajor pathological response [NMPR]) treated with neoadjuvant chemoimmunotherapy, sourced from the GEO database. Molecular analyses and immune infiltration analyses were performed using pathologic response as an endpoint. After identifying the interferon signaling subset NeoIGS, we analyzed the relationship between NeoIGS and immune scores, immune cell infiltration, and immunotherapy efficacy. A key gene in NeoIGS was screened by reveiver operating characteristic curve (ROC) analysis. Subsequently, the expression of the key gene was assessed by immunohistochemistry in 53 NSCLC patients receiving neoadjuvant *** signaling pathway expression and CD8+ T-cell infiltration were higher in the MPR group. NeoIGS predicted pathological response to neoadjuvant chemoimmunotherapy (AUC = 0.926) and also demonstrated predictive value in the ICIs monotherapy cohort. IPS and TIDE scores also confirmed NeoIGS's association with immunotherapy in the TCGA NSCLC dataset. Furthermore, patients with higher NeoIGS scores had more immune cell infiltration and increased expression of ICI targets. ROC analysis identified ATF3 as NeoIGS's key gene. In the clinical cohort, ATF3 outperformed PD-L1 in predicting pathologic response, with a 90.0% MPR rate in the high-expression *** established that a subset of interferon signaling pathways, NeoIGS, is closely associated with immunotherapy. Among them, ATF3 is the most critical gene that accurately predicts pathological remission in neoadjuvant chemoimmunotherapy.

关键词： ATF3   Metabolism   Histone modification   Post-translational modification (PTM)   Oncotherapy  

摘要： Cellular stress response is a pivotal process in tumor development and therapy. Activating transcription factor 3 (ATF3), a representative stress-responsive protein, plays pleiotropic roles in various biological processes. Over the past decade, studies have described not only the general role of ATF3 in tumor metabolism but also the complexity of ATF3 expression regulation and its associated modifications, including phosphorylation, ubiquitination, SUMOylation, and NEDDylation. Interestingly, beyond being a transcription factor, ATF3 can act as a modifier to control the ubiquitination of target molecules, such as p53, to exert its function in tumors. These advances in uncovering ATF3 biological function have yielded new insights into the cellular stress response during tumor development and will be instrumental in developing novel interventions. In this review, we update the role of ATF3 as a nexus in amino acid metabolism, lipid metabolism, glycometabolism, and other metabolic pathways in tumors;delineate the underlying mechanisms involving DNA level regulation, epigenetic regulation, and post-translational modifications of ATF3;and summarize the progression of tumor mono/combination therapies related to ATF3. In particular, we discuss the challenges that need to be addressed to provide a new conceptual framework for further understanding the potential therapeutic value of ATF3 in ongoing clinical trials.

关键词： Berberine   AMPK   ATF3   Rheumatoid arthritis   MAPK  

摘要： This study aimed to explore the protective effects of berberine against rheumatoid arthritis (RA) and clarify the role of activating transcription factor 3 (ATF3) in the mechanism of action of berberine, using a lipopolysaccharide (LPS)-stimulated SW982 human synovial cell line. Berberine treatment resulted in a concentrationdependent reduction in LPS-induced proinflammatory cytokines and matrix metalloproteinases (MMPs) in SW982 cells. These inhibitory effects were associated with increased ATF3 expression, reduced nuclear translocation of nuclear factor-kappa B (NF-kappa B), and diminished phosphorylation of mitogen-activated protein kinase (MAPK). In contrast, ATF3 knockdown reversed the suppressive effects of berberine on proinflammatory cytokines and MMP production, leading to enhanced MAPK phosphorylation;however, it had minimal impact on adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Furthermore, AMPK knockdown negated the protective effects of berberine and reduced ATF3 levels, whereas treatment with 5-aminoimidazole4-carboxamide ribonucleotide, an AMPK activator, replicated the beneficial effects of berberine. In an in vivo collagen-induced arthritis (CIA) mouse model, intraperitoneal administration of berberine significantly reduced paw edema and arthritis severity, accompanied by ATF3 induction and increased AMPK phosphorylation in the synovial tissue. These findings highlighted the pivotal role of ATF3 in mediating the protective effects of berberine in RA- and LPS-activated synoviocytes, suggesting its potential as a therapeutic agent for RA management.

关键词： Adrenocortical carcinoma   ATF3   ATF4   ER stress   Mitotane   RNAseq  

摘要： Adrenocortical Carcinoma is a rare and aggressive endocrine malignancy, that arises from cells of one of the three cortical layers of the adrenal gland. Radical surgery is the only curative treatment, even if recurrence rates are high. Therapeutic options are limited, with mitotane as the cornerstone of medical therapy. Despite 50 years of clinical use, the mechanism of action of mitotane has not yet been fully established, possibly due to the drug's susceptibility to interaction with confounding factors that reduce its biological activity. In the present study, we evaluated by RNAseq the effect of mitotane on gene expression in the H295R cell line, in an environment free of known confounding factors. Our approach allowed us to identify transcriptional deregulation of the ATF4/ATF3 axis, often involved in ER stress. These results were also validated by ddPCR in independent experiments. Mitotane-mediated ATF4 overexpression was also confirmed at the protein level. We observed how an incremental concentration of mitotane could deregulate main biological pathways. Further, we confirmed, both at RNAseq and ddPCR level, the mitotane-mediated downmodulation of genes such as STAR, CYP11A1, CYP21A2, and HSD3B2, highlighting its effect on steroid hormones biosynthesis. Through our approach, we identified biological pathways altered by mitotane in early response stages and with low drug concentrations. Some of these pathways could potentially be investigated in the future as functional biomarkers to monitor adrenocortical carcinoma treatment or as new pharmacological targets for this rare disease. © 2025 The Authors

关键词： circSLC8A1通路   ATF3通路   癫痫进程   氧化应激   铁活性   细胞活性  

摘要： 目的分析circSLC8A1介导转录激活因子3(activating transcription factor 3,ATF3)通路影响癫痫细胞氧化应激及铁活性的机制。方法采用无Mg2+方法构建人神经元-海马细胞癫痫模型,检测健康对照组和模型组细胞的circSLC8A1、ATF3表达水平,采用质粒转染方式建立敲除circSLC8A1组、敲除ATF3组、敲除circSLC8A1+过表达ATF3组、敲除ATF3+过表达circSLC8A1组,转染6h后更换正常培养基培养48h。检测并比较不同干预组的细胞活力、铁活性、活性氧(reactive oxygen species,ROS)、乳酸脱氢酶(lactate dehydrogenase,LDH)和谷胱甘肽(glutathione,GSH)差异。结果模型组细胞的circSLC8A1、ATF3、ROS、LDH表达水平及铁活性均显著高于健康对照组,细胞活力和GSH表达水平均显著低于健康对照组(P<0.05);敲除circSLC8A1可显著降低癫痫模型细胞circSLC8A1表达量,敲除ATF3可显著降低癫痫模型细胞ATF3表达量(P<0.05);敲除circSLC8A1或ATF3,可使癫痫模型细胞的细胞活力升高,铁活性降低,氧化应激反应缓解,敲除circSLC8A1并过表达ATF3可逆转上述趋势,但敲除ATF3过表达circSLC8A1并不会导致上述现象。结论circSLC8A1能够通过介导ATF3通路,对癫痫模型对细胞活性、氧化应激反应及铁活性进程产生一定影响,可为癫痫产生机制及靶向治疗提供借鉴。

关键词： ACTH   Adrenocorticotropic hormone   AD   Alzheimer's disease   AKT   Protein Kinase B/PKB   ATF3   Activating transcription factor 3   ATF6   Activating transcription factor 6   Axin2   Axin-related protein 2   AVP   Arginine vasopressin   Aβ   Amyloid β   Bax   Bcl-2-associated X protein   BBB   Blood-brain barrier   Bcl-2   B-cell lymphoma 2   BD   Bipolar disorder   BDNF   Brain-derived neurotrophic factor   BMSCs   Bone marrow mesenchymal stem cells   BrdU   Bromodeoxyuridine   Btk   Bruton's tyrosine kinase   CD86   Cluster of differentiation 86   CDKL5   Cyclin-dependent kinase-like 5   CNS   Central nervous system   Con-Exos   Exosomes from control mice   CREB   cAMP response element-binding protein   CRH   Corticotropin-releasing hormone   CRS   Chronic restraint stress   CRS-Exos   Exosomes from chronic restraint stress-induced depressed mice   CSF   Cerebrospinal fluid   CTNND1   Catenin Delta-1   CUMS   Chronic unpredictable mild stress   CUS   Chronic unpredictable stress   CVSD   Cerebral small vessel disease   CXCL8   C-X-C motif chemokine ligand 8   DA   Dopamine   DCX   Doublecortin   DG   Dentate gyrus   DIANA-miRPath   Digital Identification And Network Analysis - microRNA Pathway Analysis   DNA   Deoxyribonucleic acid   ER   Endoplasmic reticulum   ERK1/2   Extracellular signal-regulated protein kinases1/2   EVs   Extracellular vesicles   E2   Estrogen   FZD2   Frizzled class receptor 2   GCs   Glucocorticoids   GDNF   Glial cell line-derived neurotrophic factor   GFAP   Glial fibrillary acidic protein   GR   Glucocorticoid receptor   GSH   Glutathione   GSK3β   Glycogen synthase kinase 3 β   HPA   Hypothalamic-pituitary-adrenal   HSP70   Heat shock protein 70   IFN   Interferon   IFN-α   Interferon-α   IFN-γ   Interferon-γ   IGF-1   Insulin-like growth factor-1   IκB   Inhibitor of κB   IκBα   Inhibitor of κBα   IKK   IκB Kinase   IKKα   IκB kinase α   IKKβ   IκB Kinase β   IL-1β   Interleukin-1β   IL-2   Interleukin-2   IL-4   Interleukin-4   IL-6   Interleukin-6   IL-10   Interleukin-10   IL-13   Interleukin-13   IL-1Rα   Interleukin-1 receptor alpha   INOS   Inducible nitric oxide synthase   INS   Insulin   INSR   Insulin receptor   IR   Insulin resistance   IRAK4   Interleukin-1 receptor-associated kinase 4   IRS-1   Insulin receptor substrate 1   ISEV   Internatio  

摘要： Major depressive disorder, a debilitating neurological disorder, remains enigmatic in its etiology, and current treatments are still inadequate. Therefore, unraveling its pathogenesis and discovering novel therapeutics is imperative. Exosomes are small extracellular nanoscale vesicles containing biomolecules, such as lipids, proteins, and nucleic acids, and have the ability to facilitate intercellular communication. Their potential as diagnostic indicators and therapeutic agents in conditions like autoimmune diseases, cardiovascular diseases, and cancer has been increasingly recognized. This review briefly introduces the relationship between exosomes and major depressive disorder, providing a systematic overview of how exosomal constituents contribute to the pathogenesis and progression. Furthermore, it underscores the significance of exosome research for advancing diagnostic and therapeutic approaches in major depressive disorder, offering a promising avenue for developing more effective clinical strategies.

摘要： Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra and/or intracellular changes. In this study, we observed that one of the ATFs, Activating transcription factor 3 (ATF3), is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1 alpha) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. In addition, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion-conducive extracellular matrix (ECM) under hypoxic conditions. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. Interestingly, involvement of ATF3 in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Furthermore, we also show that the demethylated DNA region of intron 9a then becomes accessible to CCCTC-binding factor (CTCF). Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA Pol II pause at intron 9a via CTCF, leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results reveal a novel hypoxia-induced HIF1 alpha-ATF3-P4HA1 axis which can potentially be exploited as a therapeutic target to impede EMT and ultimately breast cancer *** induced ATF3 regulates P4HA1 e

关键词： ATF3   HPV   MMP1   SHARP1   ROS   DSBs   Cervical cancer  

摘要： BackgroundActivating Transcription Factor 3 (ATF3) is known for its tumor-suppressive properties in cervical cancer, particularly through its role in stress response and interactions with human papillomavirus (HPV) oncogenes. This study investigates ATF3's regulatory impact on metastasis-related genes, oxidative stress, and DNA damage in HPV-positive cervical cancer cells. MethodsHeLa and Ca Ski cell lines were transfected with ATF3-expressing vectors. Western blotting and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to confirm ATF3 overexpression following transfection. ROS assays and Comet assays assessed the impact of ATF3 on oxidative stress and DNA damage, while RT-qPCR was used to evaluate changes in HPV E6/E7, SHARP1, and MMP1 gene expression. ResultsATF3 overexpression led to elevated ROS levels (p < 0.02), resulting in oxidative DNA damage. These results demonstrate ATF3's cytotoxic impact on cervical cancer cells through oxidative stress and DNA damage. Additionally, ATF3 overexpression significantly decreased MMP1 expression (p < 0.03), indicating a potential anti-metastatic effect, while SHARP1 and HPV E6/E7 expression levels were not significantly altered, indicating selective gene modulation by ATF3. ConclusionThese findings reveal that ATF3 contributes to tumor suppression in cervical cancer by modulating oxidative stress and DNA damage, selectively targeting genes involved in metastasis. These findings supports ATF3's role in regulating key pathways in HPV-positive cervical cancer cells, providing a basis for further exploration of ATF3 as a target in therapeutic strategies aimed at improving outcomes in cervical cancer.

关键词： Common clinical tumors   Targeted drug screening   Personalized medicine   Patient-derived xenograft   PDX Model Database   PDX   patient-derived xenograft   ICH-GCP   International Council for Harmonization for Good Clinical Practice   NCI   National Cancer Institute   CDX   cell line-derived xenograft   CTC   scirculating tumor cells   BME   Basement Membrane Extract   EHS   Engelbreth-Holm-Swarm   LC   Lung cancer   NSCLCs   non-small cell lung cancers   LUAD   lung adenocarcinoma   LUSC   lung squamous cell carcinoma   SCLCs   small cell lung cancers   PI3K   phosphatidylinositol 3-kinase   AKT   serine/threonine kinase   HOX   homeobox   KRAS   kirsten rat sarcoma viral oncogene   HER3   human epidermal growth factor receptor 3   mTOR   mammalian target of rapamycin   ROR2   receptor tyrosine kinase-like orphan receptor 2   PM2.5   particulate matter 2.5   CDK   cyclin dependent kinase   ERK   extracellular regulated protein kinases   EGCG   epigallocatechin gallate   BRD4   bromodomain-containing protein 4   UBA1   ubiquitin-activating enzyme 1   MET   mesenchymal to epithelial transition factor   FGFR1   fibroblast growth factor receptor 1   MYCN   N-myc proto-oncogene   EGFR   epidermal growth factor receptor   CRC   Colorectal cancer   PVT1   plasmacytoma variant translocation 1   VEGFA   vascular endothelial growth factor A   TIMP2   tissue inhibitors of metalloproteinase 2   PDAP1   PDGFA-associated protein 1   PLOD2   Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase 2   SLC6A8   solute carrier family 6 member 8   MEK   mitogen-activated proteinkinase kinase   MDM2   murine double minute 2   PIM1   proviral integration site for Moloney murine leukemia virus 1   PROTAC   proteolysis targeting chimeric   HCC   Hepatocellular carcinoma   METTL5   methyltransferase 5, N6-adenosine   DANCR   differentiation antagonizing non-protein coding RNA   POSTN   Periostin   TGF-β1   transforming growth factor-β1   DPP4   dipeptidyl peptidase 4   DNAJB1   DnaJ heat shock protein family member B1   PRKACA   c-AMP dependant protein kinase A catalytic subunit α   YTHDF1   YTH N6-methyladenosine RNA binding protein 1   BCL-XL   B-cell lymphoma-XL   PHGDH   phosphoglycerate dehydrogenase   ROS1   C-ros oncogene 1   NMT1   N-myristoyl trans  

摘要： The establishment of mouse models is critical for discovering the biological targets of tumorigenesis and cancer development, preclinical trials of targeted drugs, and formulation of personalized therapeutic regimens. Currently, the patient-derived xenograft (PDX) model is considered a reliable animal tumor model because of its ability to retain the characteristics of the primary tumor at the histopathological, molecular, and genetic levels, and to preserve the tumor microenvironment. The application of the PDX model has promoted in-depth research on tumors in recent years, focusing on drug development, tumor target discovery, and precise treatment of patients. However, there are still some common questions. This review introduces the latest research progress and common questions regarding tumors with high mortality rates, focusing on their application in targeted drug screening and the formulation of personalized medical strategies. The challenges faced, improvement methods, and future development of the PDX model in tumor treatment applications are also discussed. This article provides technical guidance and comprehensive expectations for anti-cancer drug screening and clinical personalized therapy.