Molecular and Cellular Endocrinology最新文献

{"title":"MeCP2 attenuates inflammation and regulates T cell phenotype via SFRP4 suppression in preeclampsia","authors":"Mei Peng ,&nbsp;Yanting Nie ,&nbsp;Ying Luo,&nbsp;Grace Divine Milebe Nkoua,&nbsp;Shaohan Zhang,&nbsp;Hongyu Liu,&nbsp;Wen Zhang,&nbsp;Songyuan Xiao,&nbsp;Yang Zhou,&nbsp;Weisi Lai,&nbsp;Yali Deng,&nbsp;Ling Yu,&nbsp;Jinyu Liu,&nbsp;Xihong Zhou,&nbsp;Yiling Ding","doi":"10.1016/j.mce.2025.112637","DOIUrl":"10.1016/j.mce.2025.112637","url":null,"abstract":"<div><div>Preeclampsia (PE) is a major pregnancy complication characterized by an aberrant immune response. Methyl CpG binding protein 2 (MeCP2) is a potential regulator of secreted frizzled-related protein 4 (SFRP4), and both MeCP2 and SFRP4 are implicated in immune homeostasis. This study investigated the regulatory role of MeCP2/SFRP4 in immune cells in PE. A rat model of PE induced by reduced uterine perfusion pressure (RUPP) and an <em>in vitro</em> model using lipopolysaccharide (LPS)-stimulated HTR-8/SVneo cells were established. A co-culture system of LPS-challenged HTR-8/SVneo cells and T cells was also employed. MeCP2 expression was reduced and inversely correlated with SFRP4 levels in PE. MeCP2 overexpression suppressed Th1/Th17 differentiation while promoting Th2/Treg phenotypes, along with modulation of associated immune cytokines. It also enhanced colony formation, proliferation, migration, and invasion, while reducing apoptosis following co-culture. SFRP4 supplementation reversed the effects of MeCP2 overexpression on T cell proliferation and cytokine release. Collectively, these findings suggest that MeCP2 regulates T cell phenotype and inflammatory responses by inhibiting SFRP4, providing potential avenues for immunotherapeutic intervention in PE.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112637"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic modifications in maternal pancreatic islets during the period around weaning in mice","authors":"Xadeni Burgos-Gamez ,&nbsp;Paulina Morales-Castillo ,&nbsp;Alain Hernández-Vázquez ,&nbsp;Karina Pastén-Hidalgo ,&nbsp;Francisco García-Vázquez ,&nbsp;Cristina Fernandez-Mejia","doi":"10.1016/j.mce.2025.112642","DOIUrl":"10.1016/j.mce.2025.112642","url":null,"abstract":"<div><div>Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an increase in beta-cell proliferation and a significant islet expansion around the weaning period in mice. This study aims to identify transcripts associated with changes in the islets around weaning—a physiological stage previously unexplored in islets. A ribonucleic acid (RNA) sequencing analysis of the transcriptome was performed at four key time points: the end of lactation, when beta-cell proliferation increases; the day of weaning, when the hormonal and metabolic environment transitions from lactation to the non-lactating stage; the third day post-weaning, when islet area peaks, as observed in our prior studies; and in age-matched female control mice. The results revealed dynamic transcriptomic changes. The messenger ribonucleic acid (mRNA) expression levels of genes regulated by prolactin, including its receptor, signaling inhibitor <em>Cish</em>, tryptophan hydroxylase, and osteoprotegerin, increased during lactation and subsequently declined. Plasma prolactin concentrations rose during lactation, but plasma osteoprotegerin levels remained stable across groups. Notably, no changes were observed in known prolactin-regulated cyclins that positively influence the cell cycle, such as <em>Ccna2</em>, <em>Ccnb1</em>, and <em>Ccnb2</em>. However, a decrease in the expression of <em>Cdkn1a</em>, a negative regulator of the cell cycle, was noted. Surprisingly, microscopy analysis indicated increased apoptosis markers in islet peripheral cells that were negative for insulin immunostaining. This study is the first to identify transcriptomic and cellular changes around weaning, offering new insights into islet mass plasticity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112642"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental programming: Differing impact of prenatal testosterone and prenatal bisphenol-A -treatment on hepatic methylome in female sheep","authors":"John Dou ,&nbsp;Soundara Viveka Thangaraj ,&nbsp;Yiran Zhou ,&nbsp;Vasantha Padmanabhan ,&nbsp;Kelly Bakulski","doi":"10.1016/j.mce.2025.112655","DOIUrl":"10.1016/j.mce.2025.112655","url":null,"abstract":"<div><div>Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health. Using Suffolk sheep, the study involved two cohorts: one exposed to prenatal-T and the other to prenatal-BPA. Whole genome bisulfite sequencing was employed to map DNA methylation across over 22 million CpG sites. Regions with p-value&lt;10⁻⁴ and a magnitude of difference of at least 5 % methylation between groups were considered differentially methylated. Results demonstrated substantial differential methylation in the liver tissues due to both treatments, with prenatal-T causing unique epigenetic modifications distinct from those induced by prenatal-BPA. Specifically, prenatal-T treatment resulted in 53 differentially methylated regions (DMRs), of which 31 were located in gene regions, including exons. Prenatal-BPA exposure led to 32 DMRs, with 22 associated with gene regions. These modifications were associated with genes governing lipid and glucose metabolism, potentially underlying the observed metabolic disruptions such as insulin resistance and dyslipidemia. Pathway analysis revealed that genes differentially methylated due to prenatal-T were involved in cellular organization, while those affected by prenatal-BPA were enriched in signal regulation pathways. The findings underscore how prenatal exposure to steroid excess and steroid-mimics influence epigenetic landscapes, contributing to metabolic disease programming.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112655"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose tissue-specific Yap knockout exacerbates diet-induced obesity through suppression of lipolysis","authors":"Huabing Xiao ,&nbsp;Ping Jiang ,&nbsp;Fan Xia ,&nbsp;Dayu Wu ,&nbsp;Hui Huang ,&nbsp;Sihui Tu ,&nbsp;Huilan Luo ,&nbsp;Yiling Wu ,&nbsp;Qiong Duan ,&nbsp;Lingyan Zhu","doi":"10.1016/j.mce.2025.112631","DOIUrl":"10.1016/j.mce.2025.112631","url":null,"abstract":"<div><h3>Background and aims</h3><div>YAP regulates various cellular processes, including cell contact inhibition, mechanotransduction, cell differentiation and proliferation, apoptosis, and cancer progression. Although YAP suppresses adipogenesis <em>in vitro</em>, its role in obesity has not yet been completely elucidated.</div></div><div><h3>Methods and results</h3><div>In this study, we generated an adipose tissue-specific <em>Yap</em> knockout mouse model (<em>Yap</em>aKO), and found that male, but not female, <em>Yap</em>aKO mice showed an enhanced high-fat diet-induced obesity phenotype compared to control mice. Mechanistically, this effect is potentially due to suppressed lipolytic activity, which results from the decreased expression of triglyceride lipolytic enzymes, including ATGL and HSL. The inhibition of lipolytic activity led to reduced levels of circulating free fatty acids during fasting, making male mice unable to maintain core body temperature after cold exposure and showing impaired exercise capability in the fasted state. This study reveals a novel role of YAP in controlling lipolysis.</div></div><div><h3>Conclusion</h3><div>YAP is a physiological regulator of lipolysis in the adipose tissue. YAP activation in adipose tissue may facilitate lipolysis and reduce obesity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112631"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oocyte-specific Ahr deletion disrupts folliculogenesis and female fertility in mice","authors":"Pengtao Chen ,&nbsp;Jinpeng Ruan ,&nbsp;Fanzheng Xue ,&nbsp;Xuejuan Dai ,&nbsp;Chen Tang ,&nbsp;Mingyue Chen ,&nbsp;Nengming Xiao ,&nbsp;Zhijian Cai ,&nbsp;Chunyan Yang ,&nbsp;Chengyong He ,&nbsp;Wei Wang ,&nbsp;Zhenghong Zuo","doi":"10.1016/j.mce.2025.112656","DOIUrl":"10.1016/j.mce.2025.112656","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies have shown that AHR plays a role in ovarian follicle development, the precise role of oocyte-expressed AHR in female reproduction remains unclear. In this study, oocyte-specific <em>Ahr</em> knockout (cKO) mice generated by crossing the <em>Ahr</em> ^{<em>flox/flox</em>} (<em>Ahr</em> ^{<em>fl/fl</em>}) and <em>Gdf9-cre</em> transgenic mouse strains were used to answer this open question. The cKO female mice exhibited a disrupted estrous cyclicity and subfertility. Histological analyses demonstrated that oocyte AHR loss reduces the number of primary follicles while increasing the number of secondary follicles and corpus lutea in mouse ovary. Hormonal analysis revealed decreased serum estradiol and follicle-stimulating hormone, indicating a disruption of the hypothalamic-pituitary-gonadal axis in cKO mice. TUNEL and Western blotting results demonstrate that deletion of oocyte AHR also results in increased apoptosis in ovarian granulosa cells (GCs), downregulated expression of <em>Gdf9</em> and <em>Bmp15</em> in oocytes<em>,</em> and disrupted bidirectional oocyte-GC communication. In conclusion, our findings reveal that the aryl hydrocarbon receptor plays a role beyond sensing environmental chemicals and endogenous compounds and underscore a critical role of oocyte-expressed Ahr in maintain follicle development, ovarian function, and female reproductive health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112656"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-dimensional (3D) pancreatic β-cell models reveal insulin-secretion enhancing potential of green synthesized silver nanoparticles","authors":"Cigdem Aydin Acar ,&nbsp;Suray Pehlivanoglu","doi":"10.1016/j.mce.2025.112659","DOIUrl":"10.1016/j.mce.2025.112659","url":null,"abstract":"<div><div>This study synthesized silver nanoparticles using cherry stem aqueous extract (Cs-AgNPs) and evaluated their physicochemical properties, cytotoxic effects on pancreatic β-cell lines, antioxidant activity, and their potential to enhance insulin secretion in 3D pancreatic β-cell models. Cs-AgNPs were synthesized via a reaction between cherry stem extract and silver nitrate, confirmed through color change and UV–Vis spectrophotometry. Characterization using EDS, TEM, and XRD revealed spherical nanoparticles with a crystalline structure, sizes ranging from 10.93 to 31.18 nm, and an average size of 26.67 nm. Biological assessments showed dose-dependent cytotoxic effects on pancreatic β-cell lines, with reduced viability observed at ≥2 μg/mL for INS-1 cells and ≥5 μg/mL for RINm5F cells. Antioxidant activity was confirmed through ABTS assay, with an IC₅₀ value of 78.81 μg/mL. Functional studies on 3D pancreatic β-cell spheroids revealed a significant 1.6-fold increase in insulin secretion in RINm5F cells (p = 0.0166) and a modest 1.2-fold increase in INS-1 cells. The results highlight the antioxidant properties and insulin secretion enhancement potential of Cs-AgNPs, suggesting their promise for diabetes-related applications. Further research is recommended to explore their therapeutic benefits and expand their biomedical utility.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112659"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The N-terminal region of HASPIN regulates phosphorylation of AURKA and meiotic progression in spermatocytes","authors":"Haojie Li ,&nbsp;Yaoting Xu ,&nbsp;Xinyi Jiang ,&nbsp;Jie Ren ,&nbsp;Yulian Wang ,&nbsp;Xiangzheng Zhang ,&nbsp;Mengmeng Gao ,&nbsp;Longsheng Zhang ,&nbsp;Yue Wang ,&nbsp;Zongze Li ,&nbsp;Suwei Wang ,&nbsp;Tianye Wang ,&nbsp;Mengyi Wang ,&nbsp;Chenghao Situ ,&nbsp;Xuejiang Guo ,&nbsp;Hui Zhu","doi":"10.1016/j.mce.2025.112645","DOIUrl":"10.1016/j.mce.2025.112645","url":null,"abstract":"<div><div>Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this study, we found that the intrinsically disordered N-terminal domain of HASPIN is also required for this function. Mice with deletion of N-terminal amino acids (aa) 1-243 of HASPIN exhibited reduced testicular size, sperm count, and fertility. Using immunoprecipitation-mass spectrometry and phosphoproteomics analysis, we found that HASPIN could interact with AURKA and regulate its phosphorylation at T279 via its N-terminus. Taken together, our results suggest that the N-terminus of HASPIN regulates AURKA kinase activity to affect male fertility.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112645"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liraglutide induces enhanced suppression of food intake in mice lacking the growth hormone secretagogue receptor","authors":"Daniela A. Cassano ,&nbsp;Julieta Aguggia ,&nbsp;Lucía Giovanini ,&nbsp;Florencia Heredia ,&nbsp;Pablo N. De Francesco ,&nbsp;María F. Andreoli ,&nbsp;Helgi B. Schöth ,&nbsp;Abdella M. Habib ,&nbsp;Gimena Fernandez ,&nbsp;Mario Perello","doi":"10.1016/j.mce.2025.112627","DOIUrl":"10.1016/j.mce.2025.112627","url":null,"abstract":"<div><div>The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activation strongly stimulates food intake. Here, we tested the hypothesis that blocking GHSR could affect the anorectic and weight-reducing effects of liraglutide, a GLP-1R agonist widely used to treat diabetes and obesity. We first found that liraglutide induced a stronger reduction in food intake in <em>ad libitum</em>-fed GHSR-deficient mice compared to wild-type (WT) controls, regardless of sex. Liraglutide treatment also resulted in greater gastric content mass in <em>ad libitum</em>-fed GHSR-deficient mice than in WT mice. Interestingly, GLP-1R immunolabeling was elevated in the paraventricular nucleus of the hypothalamus (PVH) in GHSR-deficient mice, whereas the number of proopiomelanocortin (POMC) neurons and liraglutide-induced c-Fos activation—either in the entire arcuate nucleus or specifically within POMC neurons—remained unchanged compared to WT controls. Liraglutide-induced c-Fos expression in the lateral septum and PVH was reduced in GHSR-deficient mice. Conversely, pharmacological GHSR blockade using either JMV2959 or the endogenous antagonist/inverse agonist liver-expressed antimicrobial peptide 2 did not enhance liraglutide-induced food intake reduction. In conclusion, our findings reveal that genetic GHSR deficiency amplifies liraglutide's anorectic effects and provide new insight into the neurobiological mechanisms underlying this interaction. These results suggest that dual modulation of the GHSR and GLP-1R systems may represent a promising strategy for obesity treatment, though careful selection of GHSR-targeting agents and therapeutic protocols will be essential to optimize clinical outcomes.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112627"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The sex-chromosomes related cellular dimorphism in physiology and pathology","authors":"Cristina Antinozzi,&nbsp;Paolo Sgrò,&nbsp;Luigi Di Luigi","doi":"10.1016/j.mce.2025.112630","DOIUrl":"10.1016/j.mce.2025.112630","url":null,"abstract":"<div><div>Sex-based biological differences have a profound impact on health and disease. Historically, these disparities were primarily attributed to differences in gonadal hormones. Recent advances in biochemistry and molecular biology, however, have revealed additional contributing mechanisms—most notably, the critical role of genes located on the X and Y chromosomes. The expression of Y-linked genes, increased dosage of X-linked genes in XX compared to XY cells due to incomplete X-chromosome inactivation, genomic imprinting, and the presence of non-coding and micro-RNAs on the X chromosome are all factors that require consideration in the development of <em>in vitro</em> models addressing sex dimorphism.</div><div>In the present narrative review, we propose studies showing sex differences in vascular and cardiac cells, skeletal muscle cells, adipose tissue, liver, immune cells, cancer tissues and brain tissues. Given the absence of appropriate experimental methodologies for reproducing <em>in vitro</em> the sex differences observed <em>in vivo</em> and the limited research conducted at the cellular and molecular level to elucidate the mechanisms responsible for the observed dimorphism, the present review has two objectives. Firstly, it aims to emphasize the necessity of incorporating sex as a variable in preclinical research. Secondly, it highlights the importance of sex chromosome differences as a biological variable that can influence cell physiology and biological responses, which is crucial when conducting <em>in vitro</em> studies.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112630"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the allosteric control of androgen receptor DNA binding by its disordered N-terminal domain.","authors":"Laurens W H J Heling, Jolieke van der Veen, Adam Rofe, Eric West, Alba Jiménez-Panizo, Andrea Alegre-Martí, Vahid Sheikhhassani, Julian Ng, Thomas Schmidt, Eva Estébanez-Perpiñá, Iain J McEwan, Alireza Mashaghi","doi":"10.1016/j.mce.2025.112634","DOIUrl":"10.1016/j.mce.2025.112634","url":null,"abstract":"<p><p>The androgen receptor (AR) plays a pivotal role in male physiological development and is implicated in the pathogenesis of various diseases, including prostate cancer. Its N-terminal domain (NTD), characterized by intrinsic disorder, is essential for transcriptional activation. Despite its importance, the precise mechanisms by which the NTD regulates AR's DNA-binding activity remain incompletely understood. This research elucidates the allosteric control mediated by specific NTD subregions-the N-terminal region (NR) and the C-terminal region (CR)-over the DNA binding properties of a truncated AR construct comprising the DNA-binding and ligand-binding domains (ΔNTD-AR). Microscale Thermophoresis (MST) and single-molecule fluorescence imaging were employed to investigate these interactions. This study demonstrates that the NTD subregions exert differential modulatory effects on the kinetics and affinity of ΔNTD-AR binding to DNA. MST analyses indicated that CR reduces ΔNTD-AR DNA binding affinity concentration-dependently, whereas NR did not significantly alter affinity. Single-molecule investigations revealed NR accelerates dissociation, while CR markedly diminishes binding frequency and accelerates dissociation. Combined NR and CR exerted complex effects, synergistically reducing affinity at high concentrations and altering kinetics distinctively compared to individual subregions. Collectively, these results delineate distinct functional roles for the NR and CR subregions in allosterically modulating AR-DNA interactions. This detailed understanding of intrinsic AR regulation offers mechanistic insights into receptor function and highlights potential allosteric sites for therapeutic intervention.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112634"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}