{"title":"CYR61 and CTGF mediate the stimulatory effect of amphiregulin on COX-2 expression in human granulosa-lutein cells","authors":"Bingxin Fu , Manman Guo , Yuanyuan Jia, Xiaoyu Han, Beibei Bi, Lanlan Fang, 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}
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
{"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}
Bartlomiej Olajossy , Andrzej T. Slominski , Agnieszka Wolnicka–Glubisz
{"title":"Inhibition of the RIPK4 enhances suppression of human melanoma growth through vitamin D signaling","authors":"Bartlomiej Olajossy , Andrzej T. Slominski , 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}
Katharina Anastasia Dinter , Samantha Aurich , Luise Müller , Adhideb Ghosh , Falko Noé , Christian Wolfrum , Matthias Blüher , Anne Hoffmann , Peter Kovacs , Maria Keller
{"title":"Sarcospan, a candidate gene of fat distribution, may affect lipid storage in adipocytes","authors":"Katharina Anastasia Dinter , Samantha Aurich , Luise Müller , Adhideb Ghosh , Falko Noé , Christian Wolfrum , Matthias Blüher , Anne Hoffmann , Peter Kovacs , 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}
Muhammad Talha Khan , Muhammad Zohair , Areeba Khan , Ahmed Kashif , Sadia Mumtaz , Fiza Muskan
{"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 , Muhammad Zohair , Areeba Khan , Ahmed Kashif , Sadia Mumtaz , 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, 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}
{"title":"Aggressive pituitary tumours and pituitary carcinomas: molecular insights guiding management and the role of precision oncology","authors":"LS Lamb , HW Sim , SJ Ramus , AI McCormack","doi":"10.1016/j.mce.2025.112598","DOIUrl":"10.1016/j.mce.2025.112598","url":null,"abstract":"<div><div>Aggressive pituitary neuroendocrine tumours and pituitary carcinomas are associated with high morbidity and mortality and have limited treatment options. Increased understanding of the molecular pathogenesis of pituitary tumours has led to identification of molecular drivers of aggressive behaviour and prognostic markers, as well as identification of therapeutic targets. Mechanisms for pituitary tumourigenesis include chromosomal genomic instability, defective DNA repair, loss of cell cycle control, epigenetic changes, dysregulation of intracellular signalling pathways and alterations within the pituitary tumour immune microenvironment. Novel therapeutic treatment options including VEGF targeted therapies and immune checkpoint inhibitors have been used with varied responses. The application of precision oncology platforms to identify therapeutic targets is well described in other cancers and should be considered in the management of aggressive pituitary tumours and pituitary carcinomas. Histopathological analysis of established prognostic markers should be included in routine clinical practice.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112598"},"PeriodicalIF":3.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248774","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}
Fengyun Su , Fanhua Shi , Chun Yang , Fei Zhao , Xiaolin Geng , Xiaojing Yang , Xudong Zhao
{"title":"NOC2L inhibits trophoblast ferroptosis in preeclampsia through the p53/SLC7A11 pathway","authors":"Fengyun Su , Fanhua Shi , Chun Yang , Fei Zhao , Xiaolin Geng , Xiaojing Yang , Xudong Zhao","doi":"10.1016/j.mce.2025.112589","DOIUrl":"10.1016/j.mce.2025.112589","url":null,"abstract":"<div><h3>Background</h3><div>NOC2L is downregulated in preeclampsia (PE). However, the underlying functional mechanisms of NOC2L in the pathogenesis of PE remain unclear.</div></div><div><h3>Methods</h3><div>Cell viability, migration, and invasion were determined in hypoxia-stimulated HTR-8/SVneo cells in CCK-8, wound healing, and Transwell assays. The levels of GSH, MDA and Fe<sup>2+</sup> were measured using specific commercial kits. Lipid ROS levels were determined through C11-BODIPY staining. The protein levels were analyzed via western blotting. Additionally, a rat model of PE was used to examine the influence of NOC2L on the progression of PE and the associated ferroptosis.</div></div><div><h3>Results</h3><div>NOC2L overexpression increased the viability of hypoxia-treated trophoblast cells and increased the levels of GSH, SLC7A11, and GPX4 while simultaneously reducing Fe<sup>2+</sup>, MDA, and lipid ROS levels. Furthermore, both NOC2L overexpression and ferrostatin-1 application facilitated trophoblast migration and invasion. In contrast, NOC2L knockdown exacerbated the hypoxia-induced increase in ferroptosis and inhibited cell migratory and invasive capabilities. Notably, treatment with PFT-α, a p53 inhibitor, abolished the influence of NOC2L silencing on trophoblast cell functions. NOC2L overexpression was associated with improved blood pressure and urinary protein concentration, reduced pathological damage in the placenta, alterations in ferroptosis-related markers, and an increased survival rate in rat fetuses.</div></div><div><h3>Conclusion</h3><div>NOC2L inhibits trophoblast ferroptosis through the p53/SLC7A11 signaling pathway, potentially preventing the progression of PE.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112589"},"PeriodicalIF":3.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248776","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}
Ester Vieira Alves , Tatiane Vieira Alves , Lauro Sergio Barrozo Junior , Marcos Vinícius de Freitas Ribeiro , Adriel Felipe Freitas Nunes , Camila Luiza Rodrigues dos Santos Ricken , Ingridys Regina Borkenhagen , Bruno Vargas Teixeira Cavalheiro , Ginislene Dias , Ricardo de Oliveira , Gisele Facholi Bomfim , Júlio Cezar de Oliveira
{"title":"White beans (Phaseolus vulgaris L.) in diet reduces hypothalamic pro-inflammatory cytokines improving insulin resistance in small litter grown rats","authors":"Ester Vieira Alves , Tatiane Vieira Alves , Lauro Sergio Barrozo Junior , Marcos Vinícius de Freitas Ribeiro , Adriel Felipe Freitas Nunes , Camila Luiza Rodrigues dos Santos Ricken , Ingridys Regina Borkenhagen , Bruno Vargas Teixeira Cavalheiro , Ginislene Dias , Ricardo de Oliveira , Gisele Facholi Bomfim , Júlio Cezar de Oliveira","doi":"10.1016/j.mce.2025.112587","DOIUrl":"10.1016/j.mce.2025.112587","url":null,"abstract":"<div><div>In the present study we were interested in studying the effect of white beans (<em>Phaseolus vulgaris</em> L.) as diet supplementation on glucose-insulin and metabolic homeostasis in early overfeeding rats. Small litter (SL) was adjusted to 3 pups on post-natal day 3, while normal litter (NL) was kept with 8 pups. The milk collection and milk intake were performed, and the rat-offspring when weaned (at 22 days old), were fed a standard (NL-SD and SL-SD groups) or a white bean (2.5 % w/w) supplemented diet (NL-WB and SL-WB groups). Body weight, food and water intake were measured from weaning until adulthood (100 days old). Glucose and insulin tolerance, and intracerebroventricular insulin (10<sup>−3</sup> mmol/L) tests were performed to assess peripheral and central insulin-glucose homeostasis in adult rats. Blood, hypothalamus, visceral fat pad and lean mass were collected. Milk from SL mothers displays high content of glucose, cholesterol, triglycerides and energy (<em>P</em> < 0.05). Milk consumption by SL rat-offspring, in early stage of suckling, was higher than NL rats (<em>P<</em>0.05). At adulthood, SL-SD rats were obese, hyperphagic, dyslipidemic, hyperglycemic, glucose intolerant and IR (<em>P</em> < 0.05). At adulthood, SL-SD rats displayed central IR and higher hypothalamic pro-inflammatory (TNF-α, 43.5 %; IL-6, 78.5 % and IL-1β, 50.1 %, <em>P</em> < 0.05) cytokine. The habitual ingestion of white beans-dietary supplementation prevented all those metabolic disruptions. In summary, white beans-dietary supplementation prevented obesity and glucose-insulin homeostasis deregulation in early overfeeding rats, avoiding hypothalamic inflammatory cytokines high levels and improving insulin sensitivity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112587"},"PeriodicalIF":3.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170257","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}
Ghausiya Rehman , Amit Kumar Srivastav , Sheeba Rizvi , Ayushi Chhabra , Rakesh K. Tyagi
{"title":"Disease-associated SNP variants of THRβ: Insights into the molecular determinants of aberrant receptor function","authors":"Ghausiya Rehman , Amit Kumar Srivastav , Sheeba Rizvi , Ayushi Chhabra , Rakesh K. Tyagi","doi":"10.1016/j.mce.2025.112585","DOIUrl":"10.1016/j.mce.2025.112585","url":null,"abstract":"<div><div>Thyroid hormone receptor beta (THRβ) is a ligand-modulated transcription factor that regulates thyroid hormone (T<sub>3</sub>)-mediated genomic actions. It regulates the hypothalamus-pituitary-thyroid axis and various metabolic processes, primarily in the liver and kidney. Research has shown that genetic variations, mainly single nucleotide polymorphism (SNP) in the <em>THRB</em> gene, may be linked to diseases like resistance to thyroid hormone, thyroid-related cancers, neurological and mental disorders. Despite this revelation, a significant gap remains in understanding the impact of SNPs on THRβ cellular function and disease etiology. Thus, the present study investigated the disease-associated missense THRβ-SNPs using both <em>in silico</em> analysis and cell-based assays. The study was initiated with computational analysis of disease-associated THRβ variants to predict the effects of SNPs on receptor conformation, structure, stability, and function. The molecular docking and simulation approach then evaluated the impact of these variants on interactions with T<sub>3</sub> and RXR. Following this, an extensive investigation was conducted into the dynamics and functioning of these receptor variants to address the underlying deviations in their cellular functioning by assessing receptor-subcellular localization, response to T<sub>3</sub> hormone, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions encountered in healthy and disease states. The study emphasizes that the structural and conformational integrity of THRβ is essential for its normal function, and critical deviations are associated with several metabolic/endocrine disease states. A comprehensive analysis of these disease-associated THRβ variants suggests the prospects of personalized medicine and the development of SNP-based genomic tests. The findings may also facilitate the discovery of novel small-molecule modulators to treat thyroid-related diseases linked to THRβ dysfunction, improving diagnosis and management of disease conditions.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112585"},"PeriodicalIF":3.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151194","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}