Molecular and Cellular Endocrinology最新文献

{"title":"Ghrelin treatment and exercise improve sperm quality in rats fed an obesogenic diet:A potential link to LEAP2","authors":"E.M. Luque ,&nbsp;V.P. Carlini ,&nbsp;P. Guantay ,&nbsp;D. Machuca ,&nbsp;P. Torres ,&nbsp;N. Ramírez ,&nbsp;V. Cantarelli ,&nbsp;M. Ponzio ,&nbsp;D. Castrogiovanni ,&nbsp;M. Perelló ,&nbsp;A.C. Martini","doi":"10.1016/j.mce.2025.112608","DOIUrl":"10.1016/j.mce.2025.112608","url":null,"abstract":"<div><div>This study aimed to evaluate whether ghrelin, with or without exercise, can reverse the alterations caused by an obesogenic diet on sperm quality, metabolism, and endocrine profile with emphasis on LEAP2 levels.</div><div>Fifty five male Wistar rats were randomly assigned, from weaning to postnatal day (pnd) 103, to five groups (n = 11/group): CD (standard chow + water); ObD (chow enriched with 30 % pork fat + water with 5 % fructose); ObD + ghrelin (obesogenic diet + 6 nmol/animal/day of ghrelin from pnd 85); ObD + Exc (obesogenic diet + standardized exercise in a running wheel, 15 min/day, 3 days/week); and ObD + ghrelin + Exc.</div><div>Body weight gain was accelerated in ObD, but ghrelin and/or Exc slowed it down. At pnd 103, all treatment groups were significantly lighter than the ObD group. Metabolic parameters were impaired in ObD animals, with exercise markedly improving them, reducing cholesterol and triglyceride levels close to control values, while ghrelin exerted a modest effect, partially reducing triglycerides and the triglyceride/HDL index but leaving values still dysregulated. Sperm concentration and motility were significantly reduced in the ObD vs. CD; ghrelin and/or Exc completely reversed these detrimental effects. Plasma LEAP2 was significantly higher in the animals receiving the obesogenic diet, and, LEAP2 correlated inversely with sperm concentration, explaining 22 % of its variation. No synergistic effects were found between ghrelin and Exc.</div><div>We demonstrated for the first time the potential of ghrelin to reverse sperm quality alterations secondary to obesity. Furthermore, ghrelin exhibited weight gain-slowing effects comparable to those of Exc. We also found an association between LEAP2 and sperm concentration, which warrants further investigation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112608"},"PeriodicalIF":3.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513848","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":"Enteroendocrine cell differentiation: Implications for human disease","authors":"Elisa Saint-Denis ,&nbsp;Bianca Frintu ,&nbsp;Madelyn Goldsmith ,&nbsp;Guilherme P. Ramos ,&nbsp;Daniel Zeve","doi":"10.1016/j.mce.2025.112607","DOIUrl":"10.1016/j.mce.2025.112607","url":null,"abstract":"<div><div>Enteroendocrine cells are the most abundant hormone producing cells in humans. Though they make up less than 1 % of the gastrointestinal epithelium, these cells have a large physiological impact through the secretion of hormones that act both locally and systemically to regulate intestinal function and whole-body metabolism, among other functions. The differentiation of enteroendocrine cells from intestinal stem cells is complex, involving not only lineage, but hormonal specification. This review highlights the specific signaling pathways and transcription factors that regulate enteroendocrine cell differentiation and hormone production, integrating newer findings into our growing understanding of this process. Further, it also describes how enteroendocrine cells and their differentiation are involved and altered in human health and disease: specifically aging, inflammatory bowel disease, obesity, and diabetes mellitus. Finally, we focus on how enteroendocrine cells can be targeted to produce insulin, a growing field with significant implications. Understanding what drives enteroendocrine differentiation, both molecularly and physiologically, will provide important insights into how these cells can serve as future therapeutic targets.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112607"},"PeriodicalIF":3.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522989","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":"Gremlin 1 regulates granulosa cell apoptosis through the TGF-β/SMAD signaling pathway during bovine follicular atresia","authors":"Yupeng Xu ,&nbsp;Mingming Liu ,&nbsp;Ting Yang ,&nbsp;Baoli Zhao ,&nbsp;Yao Li ,&nbsp;Jie Wang ,&nbsp;Yiqun Wang ,&nbsp;Pengfei Lin ,&nbsp;Huatao Chen ,&nbsp;Aihua Wang ,&nbsp;Yaping Jin ,&nbsp;Keqiong Tang","doi":"10.1016/j.mce.2025.112605","DOIUrl":"10.1016/j.mce.2025.112605","url":null,"abstract":"<div><div>Gremlin 1 is a highly conserved secretory glycoprotein of the DAN family that plays significant roles in human and mouse follicular development and ovulation through both BMP-dependent and BMP-independent pathways. However, its function and mechanisms in bovine follicular development and atresia remain unclear. This study investigated its specific molecular mechanism during follicular development in bovines. Gremlin 1 protein is expressed in ovarian follicles at various developmental stages, with both its mRNA and protein levels increasing in correlation with the progression of follicular atresia. Following Si-RNA mediated knockdown of Gremlin 1 expression, a reduction in apoptosis and an enhancement in proliferative activity were observed in granulosa cells (GCs). In contrast, recombinant human Gremlin 1 (Rh-Gremlin 1) protein significantly induced apoptosis of GCs and inhibited cell proliferation. Previous studies have shown that Gremlin 1 can mediate apoptosis in a variety of cells through the TGF-β/SMAD signaling pathway. In our study, we observed that Gremlin 1 was associated with the phosphorylation levels of SMAD-2/3, and treatment with the TGF-β signaling pathway inhibitor SB431542 partially reversed Gremlin 1-induced apoptosis of GCs. Moreover, SB431542 significantly restored the proliferative viability and cell cycle progression of GCs. The results showed that Gremlin 1 was involved in follicular atresia-related processes by regulating the apoptosis and proliferation of GCs, and partially mediated this process through the TGF-β/SMAD signaling pathway. This provides a new avenue for further exploration of its role in follicular development.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112605"},"PeriodicalIF":3.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512195","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":"Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission","authors":"Ying He ,&nbsp;Xiaoyan Li ,&nbsp;Dan Kuai ,&nbsp;Huiying Zhang ,&nbsp;Yingmei Wang ,&nbsp;Kan Wang ,&nbsp;Wenyan Tian","doi":"10.1016/j.mce.2025.112606","DOIUrl":"10.1016/j.mce.2025.112606","url":null,"abstract":"<div><div>Targeted metabolomics and ELISAs shown that Mdivi-1 treatment increased the levels of steroid hormones (progesterone and estradiol) in the supernatants of KGN cell culture medium. The purpose of this study was to explore the mechanism of Mdivi-1 promoting steroid hormone synthesis in granulosa cells (GCs). In vitro experiments revealed that Mdivi-1 did not affect the total protein expression of Drp1 in KGN cells or human luteinized GCs but increased Drp1 Ser637 phosphorylation, reduced Drp1 Ser616 phosphorylation, inhibited Drp1 mitochondrial translocation, and upregulated mitochondrial fusion proteins, promoting mitochondrial fusion. In terms of energy production, Mdivi-1 increased the expression of mitochondrial complexes I and V and the ATP concentration in GCs, increasing the energy supply for steroidogenesis. Mdivi-1 exposure significantly increased the expression and mitochondrial localization of StAR and CYP11A1 in the steroid production pathway of GCs. Further in vivo experiments demonstrated that, compared with the controls, Mdivi-1 treatment significantly increased the levels of Drp1 Ser637, StAR and CYP11A1 in ovarian tissue and the serum levels of progesterone and estradiol. Taken together, these findings suggest that Mdivi-1 induces mitochondrial fusion by increasing Drp1 phosphorylation at Ser637 and weakening the interaction between Drp1 and mitochondria. Moreover, mitochondrial fusion increases the cellular bioenergetics and the expression of StAR and CYP11A1 as well as their mitochondrial localization, thereby enhancing the activity of steroidogenesis in GCs.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112606"},"PeriodicalIF":3.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506829","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":"CYR61 and CTGF mediate the stimulatory effect of amphiregulin on COX-2 expression in human granulosa-lutein cells","authors":"Bingxin Fu ,&nbsp;Manman Guo ,&nbsp;Yuanyuan Jia,&nbsp;Xiaoyu Han,&nbsp;Beibei Bi,&nbsp;Lanlan Fang,&nbsp;Jung-Chien Cheng","doi":"10.1016/j.mce.2025.112604","DOIUrl":"10.1016/j.mce.2025.112604","url":null,"abstract":"<div><div>Amphiregulin (AREG), an epidermal growth factor (EGF)-like ligand, is the predominant epidermal growth factor receptor (EGFR) ligand in human follicular fluid and mediates the effects of luteinizing hormone (LH) on ovarian function. In this study, we investigated whether AREG regulates the expression of cysteine-rich angiogenic inducer 61 (CYR61) and connective tissue growth factor (CTGF), two key matricellular proteins involved in ovarian function, and whether they mediate AREG-induced cyclooxygenase-2 (COX-2) expression. Using the human granulosa cell tumor-derived KGN cell line and primary human granulosa-lutein (hGL) cells, we demonstrated that AREG treatment upregulated CYR61 and CTGF protein levels in an EGFR-dependent manner. Mechanistic analysis revealed that AREG-induced expression of CYR61 and CTGF was mediated through the ERK1/2, AKT, CREB, and YAP signaling pathways. Inhibition of these pathways using specific inhibitors or small interfering RNA blocked AREG-induced CYR61 and CTGF expression, indicating their essential roles in this process. Moreover, knockdown of CYR61 and CTGF attenuated AREG-induced COX-2 expression, establishing their role as key mediators of AREG signaling in human granulosa cells. Finally, our results showed that LH treatment induced the expression of CYR61 and CTGF, and this induction was attenuated by EGFR inhibition. Moreover, knockdown of CYR61 and CTGF reduced LH-induced COX-2 expression. These findings provide novel insights into the molecular mechanisms by which AREG regulates ovarian function and highlight potential targets for reproductive health research.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112604"},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264011","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":"Corrigendum to \"Angiotensin II type 2 receptor mediates high fat diet-induced cardiomyocyte hypertrophy and hypercholesterolemia\" [Mol. Cell. Endocrinol. (2019), 498, 110576 (doi: 10.1016/j.mce.2019.110576)].","authors":"Vanessa M Lima, Caroline A Lino, Nathalia Senger, Tábatha de Oliveira Silva, Renata I B Fonseca, Michael Bader, Robson A S Santos, Jose Donato Júnior, Maria Luiza M Barreto-Chaves, Gabriela P Diniz","doi":"10.1016/j.mce.2025.112590","DOIUrl":"https://doi.org/10.1016/j.mce.2025.112590","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112590"},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275388","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":"Inhibition of the RIPK4 enhances suppression of human melanoma growth through vitamin D signaling","authors":"Bartlomiej Olajossy ,&nbsp;Andrzej T. Slominski ,&nbsp;Agnieszka Wolnicka–Glubisz","doi":"10.1016/j.mce.2025.112603","DOIUrl":"10.1016/j.mce.2025.112603","url":null,"abstract":"<div><div>Downregulation of Receptor-Interacting Protein Kinase 4 (RIPK4) inhibits NF-κB and Wnt/β-catenin signaling in melanoma and xenograft growth in mice. The active form of vitamin D3 (1,25-D3), in addition to regulating calcium and phosphate metabolism in humans through the vitamin D receptor (VDR), can inhibit the NF-κB signaling pathway and can affect the proliferation and differentiation of normal and malignant cells, including melanoma. An hyperactive NF-κB pathway maintains the malignant behavior of melanoma, which can be influenced by both RIPK4 and activated VDR. As their interactions affecting the response to 1,25-D3 in melanoma have not been studied, we tested whether downregulation of RIPK4 affects the sensitivity of melanoma cells to 1,25-D3. Our results have shown that both siRIPK4 and CRISPR/Cas9-mediated RIPK4 knockout increase VDR expression in melanoma cells. Furthermore, a decrease in CYP24A1 expression and an increase in 1,25 D3-induced VDR levels were observed in cells with RIPK4 downregulation. Treatment with 1,25- D3 of RIPK4.KO cells, compared to their wild-type counterparts, significantly reduced proliferation in 2D and 3D culture (MTT or ATP assay) and decreased p-p65 and cyclin D1 levels in melanoma cells. These results indicate that RIPK4 knockout may enhance the therapeutic efficacy of 1,25-D3 against melanoma, which encourages further studies on targeting RIPK4 signaling for anti-melanoma effects in preclinical models.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112603"},"PeriodicalIF":3.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258550","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":"Sarcospan, a candidate gene of fat distribution, may affect lipid storage in adipocytes","authors":"Katharina Anastasia Dinter ,&nbsp;Samantha Aurich ,&nbsp;Luise Müller ,&nbsp;Adhideb Ghosh ,&nbsp;Falko Noé ,&nbsp;Christian Wolfrum ,&nbsp;Matthias Blüher ,&nbsp;Anne Hoffmann ,&nbsp;Peter Kovacs ,&nbsp;Maria Keller","doi":"10.1016/j.mce.2025.112602","DOIUrl":"10.1016/j.mce.2025.112602","url":null,"abstract":"<div><h3>Background and aims</h3><div>Genetic and epigenetic variations in the <em>Sarcospan</em> (<em>SSPN</em>) gene are associated with parameters of fat distribution (body mass index, waist-to-hip ratio), glucose homeostasis and adipocyte size in human potentially by affecting adipogenesis. This study aims at clarifying the impact of <em>SSPN</em> on adipogenesis, particularly focusing on its promoter methylation.</div></div><div><h3>Materials and methods</h3><div>Immortalized murine epididymal preadipocytes were transfected with fluorescence-marked plasmids coding for DNMT3a, CRISPR/dCas9-Suntag and vectors carrying guide RNAs complementary to the transcription start site region and differentiated to mature adipocytes. We performed siRNA-mediated <em>Sspn</em> knockdown in epididymal preadipocytes, measured target DNA methylation using pyrosequencing and quantified transcriptional changes of <em>Sspn</em> and adipogenic genes by qPCR. Additionally, we correlated <em>SSPN</em> mRNA values and clinical characteristics from a large human adipose tissue biobank (Leipzig Obesity Biobank).</div></div><div><h3>Results</h3><div>Epigenetic editing of the <em>Sspn</em> regulatory region in preadipocytes resulted in a significant increase (up to 35 %) in DNA promoter methylation throughout adipocyte differentiation but showed only minor effects on <em>Sspn</em> expression and fat storage. Though siRNA knockdown could also not contribute to understand the role of <em>Sspn</em> in a 2D adipogenesis model, large-scale correlation analyses still indicate the gene to be a key player in fat distribution and glucose homeostasis.</div></div><div><h3>Conclusions</h3><div>Although the epigenetic downregulation of <em>Sspn</em> showed only marginal effects on adipogenesis, associations of <em>SSPN</em> expression in human adipose tissue with parameters of fat distribution and glucose homeostasis make it a promising candidate for further studies addressing metabolic processes in adipose tissue.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112602"},"PeriodicalIF":3.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258551","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":"From Gut to Brain: The roles of intestinal microbiota, immune system, and hormones in intestinal physiology and gut–brain–axis","authors":"Muhammad Talha Khan ,&nbsp;Muhammad Zohair ,&nbsp;Areeba Khan ,&nbsp;Ahmed Kashif ,&nbsp;Sadia Mumtaz ,&nbsp;Fiza Muskan","doi":"10.1016/j.mce.2025.112599","DOIUrl":"10.1016/j.mce.2025.112599","url":null,"abstract":"<div><div>The intestine plays numerous roles in the normal physiology of our body. Gut-brain axis (GBA) is a complex communication network linking the gastrointestinal (GI) tract and central nervous system (CNS). This bidirectional system integrates endocrine, neural, and immune signals, impacting host metabolism and cognition. The gut microbiota, a critical component of the GBA, significantly impacts gut hormones, neurotransmission, neural development, and other components of gut-brain-axis. The microbiota-gut-brain axis facilitates communication via metabolites such as short chain fatty acids (SCFAs), and neurotransmitters such as dopamine, γ-amino butyric acid (GABA) and serotonin. The microbiota influences gut peptide production, including ghrelin, glucagon like pepetide-1 (GLP-1), serotonin, and cholecystokinin (CCK), thereby modulating nutrient absorption and immune responses. Gut hormones such as ghrelin, CCK, GLP-1, gastric inhibitory peptide (GIP), serotonin (5-HT), neurotensin, peptide YY (PYY) and melatonin play key roles in the GBA. These hormones play several roles including modulation of appetite and satiety, metabolism of nutrients such as lipid and glucose, insulin and glucagon secretion, and influence on gut inflammation, mood, learning and cognition. The interaction between gut microbiota and these hormones underscores their role in maintaining gut-brain homeostasis. Dysbiosis, or microbial imbalance, is linked to altered stress responses, anxiety, and depressive behaviors, highlighting the therapeutic potential of microbiota modulation. Despite the significant roles of gut hormones and microbiota in the GBA, literature on their cellular and molecular mechanisms is limited, and often based on animal models. This review synthesizes current understanding of hormones secreted by the intestine, their physiological effects and the cellular and molecular mechanisms of action underlying these effects, with a focus on their roles in the GBA. By elucidating these complex relationships, the review aims to advance research and clinical applications, offering insights into gastrointestinal and systemic health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112599"},"PeriodicalIF":3.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248775","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":"Structural comparison of androstenediol recognition by the human estrogen receptor ligand binding domains","authors":"Jordan L. Pederick,&nbsp;John B. Bruning","doi":"10.1016/j.mce.2025.112588","DOIUrl":"10.1016/j.mce.2025.112588","url":null,"abstract":"<div><div>Estrogen receptors α (ERα) and β (ERβ) are ligand-regulated transcription factors that control important biological processes in humans. The endogenous steroid androstenediol possesses estrogenic activity, despite being a precursor of the primary androgen, testosterone. While androstenediol is an agonist of both ERs, it is ∼ 3-fold selective for ERβ. Additionally, it has been reported that androstenediol can repress proinflammatory responses of the central nervous system (CNS) in an ERβ-dependent manner, but the primary estrogen, estradiol (E2), cannot. As no structural characterization of the interaction between ERα or ERβ with androstenediol has been reported, the basis of ERβ selectivity, and whether this is responsible for the anti-inflammatory effects of androstenediol, remains unclear. To address these gaps in knowledge we determined crystal structures of the human ER LBDs (hERα and hERβ) complexed with androstenediol and coactivator-derived peptide. This revealed that androstenediol stabilizes the active conformation of both receptors in the same manner as E2. The binding mode of androstenediol between the hERα and hERβ LBDs is extremely similar, suggesting that subtle differences in the van der Waals interactions mediated by non-conserved residues of the ligand binding pocket confer selectivity toward hERβ. Finally, in both receptors the coactivator-derived peptide occupied the activation function 2 (AF2) surface, as observed for previous agonist-bound hER structures. Therefore, as androstenediol does not induce any distinct structural changes within the hERβ LBD compared to E2, this suggests that the hERβ-dependent anti-inflammatory effects of androstenediol on the CNS are mediated by other factors.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112588"},"PeriodicalIF":3.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144240116","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}