Archives of biochemistry and biophysics最新文献

{"title":"Molecular insights into CYP19A1 mutations and their role in estrogen production","authors":"Yoo-bin Lee,&nbsp;Changmin Kim,&nbsp;Jiyeon Hong,&nbsp;Donghak Kim","doi":"10.1016/j.abb.2025.110573","DOIUrl":"10.1016/j.abb.2025.110573","url":null,"abstract":"<div><div>Human cytochrome P450 enzyme CYP19A1, commonly referred to as aromatase, plays a critical role in estrogen biosynthesis by catalyzing the conversion of C19 androgens into aromatic C18 estrogens. Alterations in aromatase activity have been implicated in the development and progression of estrogen-dependent diseases. Genetic mutations, including nonsynonymous single nucleotide polymorphisms (SNPs), can markedly impact the catalytic function of CYP19A1. In this study, we investigated the functional implications of six CYP19A1 variants (R192H, R192Q, T201M, R264C, P308F, and M364T). These variants were generated via site-directed mutagenesis, expressed in <em>Escherichia coli</em>, and purified. The T201M, R264C, and P308F variants exhibited measurable expression levels ranging from 90 to 150nmol P450 per liter culture, whereas no detectable P450 holoenzyme was observed for the R192H, R192Q, and M364T variants. Spectral binding assays revealed typical type I spectral shifts upon androgen binding for all purified variants with tight affinity. Catalytic activities of testosterone and androstenedione aromatization were assessed by UPLC–mass spectrometry, and steady-state kinetic analyses demonstrated that T201M and R264C retained catalytic efficiencies comparable to wild-type, with efficiency ratios of 1.1–0.9 for androstenedione and 0.6–0.8 for testosterone, respectively, relative to the wild-type. In contrast, P308F showed marked reductions in catalytic efficiencies (0.2 and 0.1), driven by decreases in both <em>k</em>_cat and <em>K</em>_m values. Structural analysis indicates that the proline residue at position 308, situated within the I-helix, is likely critical for stabilizing a catalytically active conformation of the enzyme-substrate complex. These results provide valuable insights into the functional role of CYP19A1 in estrogen biosynthesis and could inform the design of innovative therapies for estrogen-related diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110573"},"PeriodicalIF":3.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalytic and structural comparisons of fatty acid dioxygenases related to cyclooxygenases and peroxidases","authors":"Ernst H. Oliw","doi":"10.1016/j.abb.2025.110574","DOIUrl":"10.1016/j.abb.2025.110574","url":null,"abstract":"<div><div>Linoleic acid (LA) 8-, 9-, and 10-dioxygenases (DOX) of microorganisms are hemoproteins, structurally related to cyclooxygenases (COX) and, occasionally, to cytochrome C peroxidase (Ccp). These DOX are often fused to cytochromes P450 for biosynthesis of diols, epoxy alcohols, and allene oxides. AlphaFold2 (AF2) predicted the tertiary structures of COX with less than 0.45 Å deviation and central α-helices of selected DOX with very high confidence. The homology with COX was compared by superposition of the tertiary structure of COX and the COX:LA complex with the substrate recognition sites. The C_α protein fold, central α-helices of COX, and catalytic Tyr residue were conserved. The substrate cavities of COX and DOX differed notably between the catalytic Tyr and the separate orifices at the protein surface. COX and 9-DOX bound fatty acids in carboxylate-out configuration, but 8- and 10-DOX in the opposite orientation. 10<em>S</em>-DOX of the cyanobacterium <em>Nostoc punctiforme</em> preserved the α-helices of COX along with amino acid residues of the active sites of COX and DOX. The 10<em>S</em>-DOX of <em>Pseudomonas aeruginosa</em> belongs to the Ccp family and the AF2 model revealed unique structural features. The AF2 models have complemented the oxygenation process with mechanistic and evolutionary information in a pioneering manner.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"773 ","pages":"Article 110574"},"PeriodicalIF":3.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motifs in the histone H3 and H4 and chromatin modifying factors are crucial to regulate the multifactorial zinc response pathway in Saccharomyces cerevisiae","authors":"Rajshree Pal ,&nbsp;Smriti Anand ,&nbsp;Santoshi Acharjee ,&nbsp;Vandana Anjana ,&nbsp;Prateeksha Thakur ,&nbsp;Ashis Biswas ,&nbsp;Raghuvir Singh Tomar","doi":"10.1016/j.abb.2025.110571","DOIUrl":"10.1016/j.abb.2025.110571","url":null,"abstract":"<div><div>Zinc is a trace element that plays a crucial role in regulating various biological processes. To identify the factors involved in maintaining zinc homeostasis, we analysed the growth of histone mutants and gene deletions of chromatin-modifying factors. Growth assays revealed that specific regions and amino acid residues of histones H3 and H4, along with several chromatin-modifying factors, are essential for survival under zinc stress. Cells lacking certain motifs within H3 and H4 or in absence of chromatin modifiers exhibited hypersensitivity to zinc. ICP-MS analysis and fluorescence microscopy using a zinc-specific probe showed that zinc sensitive histone mutants accumulate higher zinc levels. The fluorescence microscopic analysis suggests that zinc sensitive mutants of chromatin modifying factors also contain more intracellular zinc. qRT-PCR analysis revealed that zinc-sensitive mutants exhibit upregulation of <em>ZRT1</em>, a high-affinity zinc transporter. Chromatin immunoprecipitation (ChIP) experiments further demonstrated constitutive recruitment of TBP at the <em>ZRT1</em> promoter in zinc sensitive histone mutants in zinc untreated condition. Supplementation with amino acids, glutathione, and iron alleviated the zinc sensitivity, indicating a potential interplay between zinc toxicity and metabolic or redox imbalance. Notably, iron supplementation suppressed zinc-induced growth defects, implying disrupted iron homeostasis in the mutants. In summary, our findings provide evidence that specific regions of the H3 and H4 histones and chromatin-modifying factors are critical for regulating the cellular response to zinc. The mutations in histones and chromatin modifiers probably exhibit altered chromatin structure, leading to disruption in zinc metabolism.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110571"},"PeriodicalIF":3.8,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction of two key biological targets —trypsin and DNA— with phenolic Phytochemicals: Insights from molecular docking and radical scavenging potential","authors":"Duygu İnci Özbağcı","doi":"10.1016/j.abb.2025.110567","DOIUrl":"10.1016/j.abb.2025.110567","url":null,"abstract":"<div><div>Phenolic acids represent a diverse class of phytochemicals that are abundantly present in fruits, vegetables, and other plant-based sources. The wide-ranging biological properties of these compounds have stimulated considerable interest within the scientific community. Syringic and isovanillic acid, the aromatic natural phytochemicals, are found in fruits and vegetables and exhibit a range of biological activities, including antioxidant and enzyme-modulating effects. In this study, we investigated their binding interactions with biologically significant macromolecules: calf thymus DNA (CT-DNA) and trypsin. The effects of both the phenolic acids on the structure and activity of these macromolecules were analyzed using fluorescence spectroscopy, including quenching type, binding constants, binding sites, thermodynamic parameters, synchronous fluorescence, fluorescence resonance energy transfer (FRET) analysis, two-dimensional (2D), and three-dimensional (3D) fluorescence analysis, effect of metal ions), Fourier transform infrared spectroscopy (FTIR) and molecular docking techniques. The results show that both phenolic acids could bind to CT-DNA via a minor groove mode. The fluorescence experiments indicated that both the phenolic acids bind and cause quenching of trypsin fluorescence. Molecular docking simulations were carried out to examine the interaction profiles of both the phenolic acids with CT-DNA and trypsin. Results revealed that both phenolic acids bind to the DNA minor groove via hydrogen bonding and π–π interactions, with syringic acid showing slightly higher affinity. In the case of trypsin, the isovanillic acid exhibited a stronger binding energy and formed a more compact interaction pattern within the enzyme's active site. These findings support the potential of both the phenolic acids to form stable, non-covalent complexes with biologically relevant macromolecules and contribute to their observed antioxidant and enzymatic effects. The radical scavenging activity of both phenolic acids was measured via the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) method and reported in terms of their IC₅₀ value. Based on the results, it can be inferred that the radical scavenging potential of both phenolic acids is significantly affected by the number and position of their substituents.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110567"},"PeriodicalIF":3.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress on the hallmarks of radiation-induced intestinal injury: Mechanisms, biomarkers and therapeutic targets","authors":"Zixin Hu ,&nbsp;Jingzhi Zhang ,&nbsp;Haiming Li ,&nbsp;Xiaomin Wang ,&nbsp;Ganlin Zhang ,&nbsp;Huijuan Cui ,&nbsp;Jiayun Nian","doi":"10.1016/j.abb.2025.110562","DOIUrl":"10.1016/j.abb.2025.110562","url":null,"abstract":"<div><div>Radiation-induced intestinal injury (RIII) is a major factor limiting the dose in abdominal and pelvic radiotherapy. This review summarizes our current understanding of RIII, focusing on its mechanisms, biomarkers, and potential treatment targets. Radiation directly induces DNA damage in intestinal epithelial cells and contributes to excessive reactive oxygen species (ROS), which together lead to increased apoptosis and decreased regeneration of intestinal stem cells (ISCs). An impaired antioxidant system also contributes to excessive ROS levels. Damage to ISCs results in decreased mucus production and compromised tight junctions, causing damage to the intestinal barrier. Epithelial cells impairment triggers ongoing inflammation, which promotes fibrogenesis and angiogenesis, processes involved in excessive wound healing during this damage. Endothelial cells experience DNA damage and ROS injury similar to that of epithelial cells. Intestinal vascular dysfunction, including increased permeability, ischemia, and angiogenesis, is involved throughout all stages of RIII. Additionally, dysbiosis of intestinal flora is characterized by reduced diversity, an overgrowth of conditional pathogens, and a decrease in probiotics. Current treatments for RIII include anti-inflammatory drugs, antibiotics, mucosal protective agents, and probiotics. Other therapies, such as anti-ferroptosis agents and targeted drugs, are still in preclinical studies. Traditional Chinese medicine, including decoctions, single herbs, or extracts, shows potential in treating RIII. The pathophysiology of RIII involves multiple dynamic steps, each with both harmful and protective aspects. Future research should delve deeper into these dual aspects of radiation-induced damage and its associated complications.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110562"},"PeriodicalIF":3.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sacsin deletion decreases cell viscoelasticity and motility in a glial cell model of autosomal recessive spastic ataxia of Charlevoix Saguenay","authors":"Fernanda Murtinheira ,&nbsp;João Belo ,&nbsp;Ana Sofia Boasinha ,&nbsp;Tiago T. Robalo ,&nbsp;Vukosava M. Torres ,&nbsp;Francisco R. Pinto ,&nbsp;Constança Pimenta ,&nbsp;Patricia Nascimento ,&nbsp;Mario S. Rodrigues ,&nbsp;Federico Herrera","doi":"10.1016/j.abb.2025.110569","DOIUrl":"10.1016/j.abb.2025.110569","url":null,"abstract":"<div><div>Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a movement disorder caused by loss-of-function mutations in the sacsin gene. The most common hallmark of this disease is the disruption of intermediate filament networks in cells as diverse as neurons, kidney cells, fibroblasts, astroglia and microglia. Intermediate filaments are the main filaments responsible for the mechanical and viscoelastic properties of cells and tissues, but these have never been investigated in the context of ARSACS. Here, we analyzed the consequences of sacsin loss on the mechanical functions of astroglial-like C6 cells. The phenotype of C6^Sacs−/− cells was analyzed by immunocytochemistry, electron microscopy, mass spectrometry, atomic force microscopy and motility/proliferation assays. C6^Sacs−/− cells presented an abnormal cytoskeletal and organelle distribution, global proteome alterations linked to cell motility and mechanics, a significant decrease in cell elasticity in the cytoplasm, and a striking reduction in cell motility. These mechanical alterations in glial-like cells could be especially relevant for neuroinflammation and glial scar formation upon CNS injury. Our results support a possible role for alterations in glial functions in ARSACS and provide new tools for understanding the glial-specific mechanisms involved in this movement disorder.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110569"},"PeriodicalIF":3.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial proteomics reveals multiple mechanisms of mitochondrial damage in renal tubules during sepsis-induced acute kidney injury","authors":"Jiarou Li ,&nbsp;Jingjing Bai ,&nbsp;Shanpeng Cui ,&nbsp;Zheng Han ,&nbsp;Tiantian Liu ,&nbsp;Yansong Liu ,&nbsp;Chunming Guan ,&nbsp;Junbo Zheng ,&nbsp;Hongliang Wang","doi":"10.1016/j.abb.2025.110566","DOIUrl":"10.1016/j.abb.2025.110566","url":null,"abstract":"<div><div>Sepsis-associated acute kidney injury (SA-AKI) is a common critical illness in clinical practice with a high mortality rate and is closely related to the clinical outcomes of critically ill patients. The microstructure of the kidney is highly complex, and targeted proteomic analysis of renal tubules can help us study the pathological process of SA-AKI. In the present study, we accurately separated, collected, and compared the proximal tubular structures of mice with SA-AKI and healthy mice using spatial proteomics and mass spectrometry (MS) techniques. We identified 126 upregulated and 105 downregulated proteins, indicating that damage to the SA-AKI process occurred primarily in the mitochondria. The functions of significantly differentially expressed proteins such as SCL34A1 and HO-1 were validated in the HK-2 cell line, and several pathways of mitochondrial dysfunction were observed: 1. Reduced phosphate led to oxidative phosphorylation disorders. 2. The Fenton reaction damaged the mitochondria, and 3. Excessive mitochondrial autophagy provided a novel potential target for the treatment of septic kidney injury. The MS proteomic data were deposited in the ProteomeXchange Alliance (<span><span>https://proteomecentral.proteomexchange.org</span><svg><path></path></svg></span>) using the iProX partner repository with the dataset identifier IPX0008335000.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110566"},"PeriodicalIF":3.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PACAP/PAC1R activation promotes group 2 innate lymphoid cells-dependent allergic rhinitis via ERK pathway","authors":"Huigang Wang ,&nbsp;Yifei Ma ,&nbsp;Jianyao Li ,&nbsp;Qingming Bao ,&nbsp;Guodong Yu","doi":"10.1016/j.abb.2025.110564","DOIUrl":"10.1016/j.abb.2025.110564","url":null,"abstract":"<div><div>Allergic rhinitis (AR) is a T helper type 2 (Th2)-mediated inflammatory disease. It has been reported that Group 2 innate lymphoid cells (ILC2s) may contribute to the pathogenesis of AR. While Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) has demonstrated anti-inflammatory properties in allergic contact dermatitis, its regulatory effects on ILC2s remain unclear. This study aimed to investigate the regulatory role of PACAP in ICL2 proliferation under allergic inflammation. In an ovalbumin (OVA)-induced AR mouse model, we observed significant elevations in both PACAP levels and ILC2 populations. Both <em>in vivo and in vitro</em> experiments confirmed that PACAP effectively promoted the expansion of IL-5⁺ and IL-13⁺ ILC2s subsets and enhances ILC2 proliferation. PACAP receptor PAC1R knockdown or PAC1R receptor antagonist PA-8 markedly suppressed ILC2s proliferation and cytokine production. Furthermore, <em>in vivo</em> experiments demonstrated that PACAP inhibition reduced ILC2 proliferation, thereby alleviating nasal mucosal inflammatory responses, confirming that PACAP exacerbates allergic inflammation through PAC1R-dependent activation of ILC2s. Mechanistic studies revealed that PACAP/PAC1R signaling activated the ERK pathway, as evidenced by upregulated p-ERK expression and increased IL-5/IL-13 secretion in ILC2s. These effects were effectively reversed by ERK inhibitor PD98059. Importantly, both PAC1R knockdown and ERK inhibition significantly decreased p-ERK expression and ILC2s proliferation, while ameliorating AR pathological features. Our findings revealed that PACAP/PAC1R activation promoted ILC2s proliferation and allergic inflammation through ERK pathway, which provides novel insights into the regulation of ILC2s and potential therapeutic targets in allergic rhinitis.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110564"},"PeriodicalIF":3.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in traditional Chinese medicine: Harnessing natural products for liver disease through autophagy modulation","authors":"Jiayu Wen ,&nbsp;Qiwen Xiang ,&nbsp;Yan Chen ,&nbsp;Tingting Hu ,&nbsp;Xiaoju Ma ,&nbsp;Yan Huang ,&nbsp;Chaolong Rao","doi":"10.1016/j.abb.2025.110565","DOIUrl":"10.1016/j.abb.2025.110565","url":null,"abstract":"<div><div>Globally, liver disease has emerged as a significant contributor to morbidity and mortality. The onset and progression of liver diseases are intricately linked to the modulation of autophagy, a highly conserved cellular process. Autophagy involves the systematic degradation and recycling of intracellular components, thereby maintaining cellular homeostasis. As a dynamic regulatory mechanism, autophagy plays a crucial bidirectional role in the pathogenesis of liver diseases. Natural products derived from Traditional Chinese Medicine (TCM) are abundant in nature and possess unique chemical structures and biological properties, which confer a diverse range of pharmacological activities, as demonstrated by extensive research. In recent years, pharmacological studies have revealed an additional potential function of these natural products: the regulation of autophagy. Investigating the relationship between liver diseases and autophagy can enhance our understanding of the molecular mechanisms underlying liver disease pathogenesis, providing a theoretical foundation for the development of novel therapeutic strategies targeting autophagy. This review comprehensively synthesizes current knowledge on the roles of TCM-derived natural products in liver diseases and autophagy. It further explores the mechanisms by which these natural products modulate autophagy in the context of liver diseases, including key signaling pathways such as AMPK, PI3K/Akt/mTOR, and ROS, as well as critical molecular targets like p62 and Beclin-1. By summarizing and analyzing the regulatory effects of natural products on liver diseases through autophagy, this review aims to inspire innovative approaches for the development of autophagy-based therapeutics for liver diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110565"},"PeriodicalIF":3.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deoxypodophyllotoxin induces apoptosis in non-small cell lung cancer cells by targeting the glucocorticoid receptor","authors":"Jae-Hoon Jeong ,&nbsp;Shin-Hyung Park","doi":"10.1016/j.abb.2025.110561","DOIUrl":"10.1016/j.abb.2025.110561","url":null,"abstract":"<div><h3>Aims</h3><div>Deoxypodophyllotoxin (DPT) has been reported to exhibit diverse pharmacological activities, including anticancer effects. This study aimed to elucidate the novel molecular mechanisms underlying the anticancer properties of DPT.</div></div><div><h3>Methods</h3><div>The effects of DPT on non-small cell lung cancer (NSCLC) cell proliferation and apoptosis were assessed using MTT assays, colony formation assays, flow cytometry, and western blotting. Target prediction, molecular docking simulations, and gene ontology analysis were performed to identify the molecular target of DPT and evaluate the functional relevance of DPT-associated genes in NSCLC. The role of TSC22D3 in the anticancer effects of DPT was examined by overexpressing TSC22D3.</div></div><div><h3>Results</h3><div>DPT inhibited NSCLC cell proliferation and colony formation while inducing apoptosis, as evidenced by increased sub-G1 DNA content, annexin V-positive cells, and cleaved PARP and caspase-3 expression. Notably, glucocorticoid receptor (GR) was identified as a potential molecular target of DPT. Eight genes commonly associated with NSCLC, DPT, and GR were found to negatively regulate the steroid hormone receptor signaling pathways. Molecular docking demonstrated that DPT binds to the GR ligand-binding domain with low binding energy. DPT suppressed dexamethasone-induced NSCLC cell proliferation and TSC22D3 expression, a GR target gene, with TSC22D3 overexpression partially rescuing cell viability. GR inhibition by mifepristone mimicked the effects of DPT. High GR expression correlated with shorter overall survival in various cancers.</div></div><div><h3>Conclusions</h3><div>These findings suggest that DPT exerts its anticancer effects by disrupting the GR/TSC22D3 axis in NSCLC cells, highlighting its potential as a therapeutic agent for GR-associated cancers.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"772 ","pages":"Article 110561"},"PeriodicalIF":3.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}