Exploring the Therapeutic Potential of the DOT1L Inhibitor EPZ004777 Using Bioinformatics and Molecular Docking Approaches in Acute Myeloid LeukemiaKivrak, Nalkiran, Sevim Nalkiran
Curr Issues Mol Biol (2025) 47 (3)
Abstract: Acute myeloid leukemia (AML) is a malignancy characterized by the clonal expansion of hematopoietic stem and progenitor cells, often associated with mutations such as NPM1. DOT1L inhibitors have shown potential as new therapeutic opportunities for NPM1-mutant AML. The aim of this study was to investigate potential alternative targets of the small-molecule inhibitor EPZ004777, in addition to its primary target, DOT1L, using RNA sequencing data from the NCBI-GEO database (GSE85107).Differentially expressed genes (DEGs) were identified through bioinformatic analysis, followed by pathway enrichment analysis to uncover the relevant biological pathways. Additionally, molecular docking analysis was conducted to assess the binding affinity of EPZ004777 with the proteins CT45A3, HOXA4, SNX19, TPBG, and ZNF185, which were identified as significantly DEGs. The protein structures were obtained from AlphaFold and the Protein Data Bank.EPZ004777 significantly altered gene expression. Oncofetal genes (CT45A3, TPBG) and genes associated with oncogenic pathways (HOXA4, ZNF185, SNX19) were downregulated, while the pro-apoptotic gene BEX3 was upregulated. Pathway enrichment analysis revealed the suppression of the Rap1 signaling pathway and cell adhesion molecules, which may reduce the invasiveness of AML cells. Additionally, upregulation of immune-related pathways suggests enhanced anti-tumor immune responses. Molecular docking analysis demonstrated that EPZ004777 has strong binding potential with SNX19, TPBG, and ZNF185 proteins.EPZ004777 has been identified as a potent modulator of SNX19, TPBG, and ZNF185 associated with apoptosis and tumor progression in AML.
Identification of glycolysis-related gene signatures for prognosis and therapeutic targeting in idiopathic pulmonary fibrosisGao, Sun, Hu
et alFront Pharmacol (2025) 16, 1486357
Abstract: Glycolysis plays a crucial role in fibrosis, but the specific genes involved in glycolysis in idiopathic pulmonary fibrosis (IPF) are not well understood.Three IPF gene expression datasets were obtained from the Gene Expression Omnibus (GEO), while glycolysis-related genes were retrieved from the Molecular Signatures Database (MsigDB). Differentially expressed glycolysis-related genes (DEGRGs) were identified using the "limma" R package. Diagnostic glycolysis-related genes (GRGs) were selected through least absolute shrinkage and selection operator (LASSO) regression regression and support vector machine-recursive feature elimination (SVM-RFE). A prognostic signature was developed using LASSO regression, and time-dependent receiver operating characteristic (ROC) curves were generated to evaluate predictive performance. Single-cell RNA sequencing (scRNA-seq) data were analyzed to examine GRG expression across various cell types. Immune infiltration analysis, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were performed to elucidate potential molecular mechanisms. A bleomycin (BLM)-induced pulmonary fibrosis mouse model was used for experimental validation via reverse transcription-quantitative polymerase chain reaction (RT-qPCR).14 GRGs (VCAN, MERTK, FBP2, TPBG, SDC1, AURKA, ARTN, PGP, PLOD2, PKLR, PFKM, DEPDC1, AGRN, CXCR4) were identified as diagnostic markers for IPF, with seven (ARTN, AURKA, DEPDC1, FBP2, MERTK, PFKM, SDC1) forming a prognostic model demonstrating predictive power (AUC: 0.831-0.793). scRNA-seq revealed cell-type-specific GRG expression, particularly in macrophages and fibroblasts. Immune infiltration analysis linked GRGs to imbalanced immune responses. Experimental validation in a bleomycin-induced fibrosis model confirmed the upregulation of GRGs (such as AURKA, CXCR4). Drug prediction identified inhibitors (such as Tozasertib for AURKA, Plerixafor for CXCR4) as potential therapeutic agents.This study identifies GRGs as potential prognostic biomarkers for IPF and highlights their role in modulating immune responses within the fibrotic lung microenvironment. Notably, AURKA, MERTK, and CXCR4 were associated with pathways linked to fibrosis progression and represent potential therapeutic targets. Our findings provide insights into metabolic reprogramming in IPF and suggest that targeting glycolysis-related pathways may offer novel pharmacological strategies for antifibrotic therapy.Copyright © 2025 Gao, Sun, Hu, Song, Liu, Zou, Zhu and Cheng.
Identification and validation of a novel autoantibody biomarker panel for differential diagnosis of pancreatic ductal adenocarcinomaMowoe, Allam, Nqada
et alFront Immunol (2025) 16, 1494446
Abstract: New biomarkers are urgently needed to detect pancreatic ductal adenocarcinoma (PDAC) at an earlier stage for individualized treatment strategies and to improve outcomes. Autoantibodies (AAbs) in principle make attractive biomarkers as they arise early in disease, report on disease-associated perturbations in cellular proteomes, and are static in response to other common stimuli, yet are measurable in the periphery, potentially well in advance of the onset of clinical symptoms.Here, we used high-throughput, custom cancer antigen microarrays to identify a clinically relevant autoantibody biomarker combination able to differentially detect PDAC. Specifically, we quantified the serological AAb profiles of 94 PDAC, chronic pancreatitis (CP), other pancreatic- (PC) and prostate cancers (PRC), non-ulcer dyspepsia patients (DYS), and healthy controls (HC).Combinatorial ROC curve analysis on the training cohort data from the cancer antigen microarrays identified the most effective biomarker combination as CEACAM1-DPPA2-DPPA3-MAGEA4-SRC-TPBG-XAGE3 with an AUC = 85·0% (SE = 0·828, SP = 0·684). Additionally, differential expression analysis on the samples run on the iOme™ array identified 4 biomarkers (ALX1-GPA33-LIP1-SUB1) upregulated in PDAC against diseased and healthy controls. Identified AAbs were validated in silico using public immunohistochemistry datasets and experimentally using a custom PDAC protein microarray comprising the 11 optimal AAb biomarker panel. The clinical utility of the biomarker panel was tested in an independent cohort comprising 223 PDAC, PC, PRC, colorectal cancer (CRC), and HC samples. Combinatorial ROC curve analysis on the validation data identified the most effective biomarker combination to be CEACAM1-DPPA2-DPPA3-MAGEA4-SRC-TPBG-XAGE3 with an AUC = 85·0% (SE = 0·828, SP = 0·684). Subsequently, the specificity of the 11-biomarker panel was validated against other cancers (PDAC vs PC: AUC = 70·3%; PDAC vs CRC: AUC = 84·3%; PDAC vs PRC: AUC = 80·2%) and healthy controls (PDAC vs HC: AUC = 80·9%), confirming that this novel AAb biomarker panel is able to selectively detect PDAC amongst other confounding diseases.This AAb panel may therefore have the potential to form the basis of a novel diagnostic test for PDAC.Copyright © 2025 Mowoe, Allam, Nqada, Bernon, Gandhi, Burmeister, Kotze, Kahn, Kloppers, Dharshanan, Azween, Maimela, Townsend, Jonas and Blackburn.
Proteomic Approach Using DIA-MS Identifies Morphogenesis-Associated Proteins during Cardiac Differentiation of Human iPS CellsUrasawa, Kawasaki
ACS Omega (2025) 10 (1), 344-357
Abstract: Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have potential applications in regenerative medicine. The quality by design (QbD) approach enables the efficiency and quality assurance in the manufacturing of hiPSC-derived products. It requires a molecular understanding of hiPSC differentiation throughout the differentiation process; however, information on cardiac differentiation remains limited. Proteins associated with the early stages of cardiac differentiation would be useful in the cardiomyocyte quality assessment. Here, we performed quantitative proteomics of hiPSC intermediate cells in the early phase of cardiac differentiation to better understand their molecular characteristics. Proteomic profiles suggested that day 5-7 cells were in the morphogenetic stage of cardiac differentiation. Trophoblast glycoprotein (TPBG) was the most up-regulated protein in the morphogenetic stage; it was previously shown to be up-regulated during differentiation into neural stem cells. Proteomics of TPBG-knockdown cells revealed that TPBG is involved in cell proliferation and is related to the cardiomyocyte yield, suggesting that it could be used as a marker in QbD development. Our approach helps us understand the molecular basis of hiPSC differentiation and could be a powerful tool in QbD-based manufacturing.© 2024 The Authors. Published by American Chemical Society.
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