Molecular and Cellular Endocrinology最新文献

{"title":"The role of PLIN2 gene in macrophages and its effect on acute pancreatitis.","authors":"Lihua Wang, Wenwen Jin, Feng Cheng, Feiyan Cui","doi":"10.1016/j.mce.2026.112934","DOIUrl":"10.1016/j.mce.2026.112934","url":null,"abstract":"<p><strong>Background and objective: </strong>Acute pancreatitis (AP) is a severe inflammatory disease with limited therapeutic options. This study aimed to investigate the role of Perilipin 2 (PLIN2) in macrophage polarization and its impact on AP progression.</p><p><strong>Methods: </strong>An AP mouse model was established using sodium taurocholate. In vitro, pancreatic acinar cells were treated with lipopolysaccharide (LPS) and caerulein (CAE) and co-cultured with RAW 264.7 macrophages. Pancreatic acinar cells were treated with lipopolysaccharide (LPS) and caerulein (CAE). Techniques included immunohistochemistry (IHC), Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays to assess macrophage polarization, lipid deposition, and cell damage.</p><p><strong>Results: </strong>In AP, PLIN2 expression was significantly upregulated, correlating with enhanced M1 macrophage polarization and excessive lipid droplet accumulation in pancreatic tissue. Genetic knockdown of PLIN2 effectively reduced lipid deposition, suppressed pro-inflammatory M1 polarization, and promoted anti-inflammatory M2 macrophage polarization, leading to marked attenuation of pancreatic cell damage and apoptosis. Notably, these protective effects were counteracted by the overexpression of cyclic GMP-AMP synthase (cGAS), which restored lipid deposition and M1 polarization.</p><p><strong>Conclusions: </strong>PLIN2 regulates macrophage polarization and lipid metabolism in AP, with its knockdown alleviating tissue damage by suppressing M1 polarization and promoting M2 polarization, suggesting its potential as a therapeutic target for AP management.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112934"},"PeriodicalIF":3.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183187","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":"Expression of Concern: \"Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway\" [MCE 437 (2016) 68-279].","authors":"","doi":"10.1016/j.mce.2026.112916","DOIUrl":"https://doi.org/10.1016/j.mce.2026.112916","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112916"},"PeriodicalIF":3.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075351","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":"Growth hormone enhances mitochondria biogenesis and endows mitochondrial thermogenesis in murine adipocytes","authors":"Esha Sadiq ,&nbsp;Yinghao Liu ,&nbsp;Ni Li ,&nbsp;Chen Zong ,&nbsp;Xiaojie Li ,&nbsp;Tianfu Yu ,&nbsp;Zeqing Pu ,&nbsp;Luqman Alameri ,&nbsp;Zhuoxuan Li ,&nbsp;Siying Li ,&nbsp;Xiangdong Wang ,&nbsp;Ruxing Zhao","doi":"10.1016/j.mce.2026.112758","DOIUrl":"10.1016/j.mce.2026.112758","url":null,"abstract":"<div><div>Growth hormone (GH) can reduce the size of white adipocytes in vivo and in vitro. This catabolic effect was previously believed to be related to the breakdown of stored triglycerides into free fatty acids. However, little is known about its effects on mitochondria in adipose or adipocytes. We thus examined effects of GH on mitochondrial number change and metabolic changes in fat of diet induced obese mice as well as 3T3-L1 adipocytes. We first found in vitro GH increase the density of mitochondria in 3T3-L1 adipocytes. We figured out that GH enhanced the expression of mitochondria biogenesis related genes, such as peroxisome proliferative activated receptor gamma coactivator 1 alpha (Pgc1α), DNA polymerase gamma (Polg) and transcription factor A of mitochondria (Tfam) in vitro and in vivo. To explore the underlying mechanism, we further confirmed that the enhanced expression of these proteins was dependent on the three pathways of GH signaling transduction and that GH enhanced the promoter transactivation of Pgc1α or Polg. We also found that GH increased the cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) and uncoupling protein 1 (UCP1) expression by enhancing the promoter transactivation of Cidea. We further elucidated that GH induced UCP1 expression was dependent on CIDEA using CRISPR-Cas9 technique. We therefore conclude that GH has effects on reducing adipocyte size via promoting PGC1α and POLG mediated mitochondrial biogenesis, and also on increasing UCP1 expression via CIDEA. Making adipocytes browning by GH or its analogs may provide a therapeutic strategy for metabolic diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"616 ","pages":"Article 112758"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161780","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":"Estradiol promotes trophoblasts syncytization by upregulating ESR2/SP1 transcription factor-mediated poFUT2 expression","authors":"Yaqi Li ,&nbsp;Yuyu Lei ,&nbsp;Yu Chen ,&nbsp;Luyao Wang ,&nbsp;Yanbo Wang ,&nbsp;Wenbo Wang ,&nbsp;Jiao Wang ,&nbsp;Shuai Liu","doi":"10.1016/j.mce.2026.112757","DOIUrl":"10.1016/j.mce.2026.112757","url":null,"abstract":"<div><div>The multinucleated syncytiotrophoblast (STB) at the maternal-fetal interface is formed through the continuous fusion of mononucleated cytotrophoblasts (CTBs). Estradiol and protein glycosylation are known to participate in trophoblast syncytialization. O-fucosyltransferase 2 (poFUT2), which catalyzes protein O-fucosylation, has been implicated in placental development. However, the exact role of poFUT2 in trophoblast syncytialization remains unclear. The aim of the present study is to investigate the function of the estradiol-poFUT2 axis in trophoblast syncytialization. Here, by applying immunohistochemistry, we found that poFUT2 expression was decreased in syncytiotrophoblast of placental tissues from preeclampsia patients. Employing a cell-model to induce trophoblast syncytialization <em>in vitro</em>, we demonstrated that poFUT2 promotes trophoblast cell fusion. Mechanistically, during pregnancy, elevated estradiol upregulated the expression of poFUT2 and enhanced syncytium formation. Chromatin immunoprecipitation and co-immunoprecipitation assays indicated that the regulation depends on the participation of SP1 in the estrogen receptor 2 (ESR2)-mediated regulation of the poFUT2 gene. Conclusively, our findings demonstrated that estradiol upregulated poFUT2 expression via the ESR2/SP1 complex, increasing trophoblast cell differentiation and fusion.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"616 ","pages":"Article 112757"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165878","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":"Thyroid hormones drive central nervous system remodelling during flatfish metamorphosis","authors":"Aurora Olvera ,&nbsp;Carlos Carballo ,&nbsp;I. Lazcano ,&nbsp;Aurea Orozco ,&nbsp;Manuel Manchado ,&nbsp;Deborah Mary Power","doi":"10.1016/j.mce.2026.112759","DOIUrl":"10.1016/j.mce.2026.112759","url":null,"abstract":"<div><div>Flatfish metamorphosis is an abrupt post-embryonic transformation driven by thyroid hormones (THs), in which a bilaterally symmetric pelagic larvae becomes an asymmetric benthic juvenile. While the craniofacial changes associated with eye migration during metamorphosis are well documented, the role of THs in central nervous system (CNS) remodelling remains poorly understood. Here we investigated the role of THs on CNS remodelling during metamorphosis of the flatfish, <em>Solea senegalensis</em>, by integrating high-throughput transcriptomic analysis with experimental manipulation of TH availability using an inhibitor of hormone synthesis, methimazole (MMI) or exogenous T4. Transcriptome profiling revealed 567 differentially expressed gene transcripts associated with TH-levels involved in CNS development, neuronal and glial differentiation, migration, myelination and metabolism. Key CNS-related factors such as <em>klf9</em>, <em>sox9</em>, <em>mbp</em>, and <em>plp</em> were strongly down-regulated in MMI-treated larvae. Cell proliferation assays further demonstrated increased interocular neural proliferation under hypothyroidism, consistent with impaired differentiation. Region-specific analyses of the head and body uncovered distinct patterns of TH signalling involving <em>dio2</em>, <em>dio3</em>, <em>thra</em>, <em>thrb</em>, and <em>mct8,</em> underscoring the spatial complexity of endocrine regulation. These results highlight that THs are crucial for both morphological remodelling and CNS plasticity during flatfish metamorphosis, underscoring their conserved role in vertebrate brain development.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"616 ","pages":"Article 112759"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181100","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":"Comparative analysis of melatonin and sildenafil in a rat model of pulmonary arterial hypertension: Insights into oxidative stress, inflammation, and mitochondrial biogenesis","authors":"Silvio Tasca,&nbsp;Patrick Türck,&nbsp;Daniela Drosdowski,&nbsp;Cristina Campos Carraro,&nbsp;Adriane Belló-Klein,&nbsp;Alexandre Luz de Castro,&nbsp;Alex Sander da Rosa Araujo","doi":"10.1016/j.mce.2026.112760","DOIUrl":"10.1016/j.mce.2026.112760","url":null,"abstract":"<div><div>Pulmonary artery hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to the augmented afterload of the right ventricle (RV), hypertrophy, and heart failure. Oxidative stress and inflammation in the RV may be involved in the physiopathology of PAH. Because of their antioxidant properties, melatonin and sildenafil could be possible therapeutic agents for the treatment of PAH. Therefore, the present study evaluated the protective effects of melatonin against oxidative stress, inflammation, and mitochondrial biogenesis in the RV of rats with PAH. Wistar rats were divided into four groups: control (CTR), monocrotaline (MCT), monocrotaline treated with sildenafil (MCT + SIL), and monocrotaline treated with melatonin (MCT + MEL). PAH was induced using a single dose of MCT (60 mg/kg, i. p.). Sildenafil citrate (50 mg/kg/day) and melatonin (10 mg/kg/day) were then administered by gavage, beginning on the first day of the experimental protocol. On the day 21, echocardiographic, morphometric, oxidative/nitrosative stress and Western blotting analyses were performed. Animals that received melatonin or sildenafil demonstrated an increased tricuspid annular plane systolic excursion (TAPSE) when compared with non-treated animals, indicating an improvement in RV contractility. Both melatonin and sildenafil treatment decreased lipid peroxidation (LPO) and reestablished sulfhydryl levels. Melatonin administration decreased the protein expression level of nuclear factor kappa beta (NF-κB), while sildenafil decreased xanthine oxidase expression. Both treatments increased peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1α) expression. Based on our findings, melatonin showed a protective effect similar to sildenafil in the RV of a rats model of PAH.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"616 ","pages":"Article 112760"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181030","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":"Triploidy alters hormonal and paracrine signaling to promote male development in zebrafish","authors":"Aarón Torres-Martínez ,&nbsp;Tomáš Tichopád ,&nbsp;Martin Pšenička ,&nbsp;Roman Franěk","doi":"10.1016/j.mce.2026.112740","DOIUrl":"10.1016/j.mce.2026.112740","url":null,"abstract":"<div><div>Sex differentiation in zebrafish is governed by a complex interplay of genetic and endocrine signals. Triploid zebrafish, which are largely sterile, consistently develop as males, but the underlying mechanisms remain elusive. Here, we combined histological and transcriptomic analyses to examine how triploidy and exposure to 17α-ethinylestradiol (EE2) modulate sex differentiation in zebrafish. Triploidy disrupted hormonal and paracrine signaling, with downregulation of <em>fshr</em> and <em>amh</em>, upregulation of <em>igf3</em>, potential activation of β-catenin pathway, and suppression of <em>ptger2a</em> and <em>dio1</em>, resulting in complete masculinization. In diploids, EE2 exposure resulted in a wide range of gonadal phenotypes, from testes and ovotestes to fully developed ovaries, reflecting the complexity and variable sensitivity of zebrafish sex differentiation to hormonal stimuli. Potential mechanistic insights underlying these outcomes are provided. By contrast, long exposure of triploid zebrafish to EE2 promoted the expansion of early germ cells, but failed to induce ovarian differentiation, suggesting a fixed male trajectory induced by triploidy. Triploids also showed a distinct endocrine state, lacking the EE2-induced suppression of <em>cyp11c1</em> observed in diploids, suggesting altered corticosteroid homeostasis that may reinforce masculinization. Both triploidy and EE2 administration altered meiosis and spermiogenesis, consistent with the downregulation of <em>klhl10</em> and constrained retinoic acid signaling through <em>dhrs3a</em> and/or <em>cyp26b1</em>. At the molecular level, both triploidy and EE2 converged on suppression of early steroidogenic genes, including <em>star</em> and <em>cyp11a1</em>, indicating limited androgen and estrogen biosynthesis. Together, these findings reveal how triploidy reshapes endocrine regulation and responsiveness and reveal shared and unique molecular pathways by which EE2 influences zebrafish gonadal fate.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112740"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086448","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 impact of maternal vitamin D deficiency during pregnancy and lactation on autism-like behavior in offspring","authors":"Xiao-Yue Song ,&nbsp;Hong-Ning He ,&nbsp;Lin-Jing Tuo ,&nbsp;Bo Wang ,&nbsp;Heng Zhang ,&nbsp;De-Xiang Xu","doi":"10.1016/j.mce.2026.112737","DOIUrl":"10.1016/j.mce.2026.112737","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and stereotyped behaviors. Many epidemiological studies have found a potential relationship between vitamin D deficiency (VDD) and ASD. However, the mechanism remains unclear. In this study, a VDD model was established by feeding a vitamin D-depleted diet to 5-week-old female mice, from their adulthood through pregnancy to end of lactation. Social deficits, repetitive stereotyped behaviors and anxiety-like behaviors were evaluated in the offspring. The results showed the number of buried marbles was increased in the female offspring of the VDD group. Social defects were observed in both male and female offspring in the VDD group. Mechanistically, several markers of cell proliferation, such as Pcna and Ki67, were upregulated. And the number of TBR2⁺ cell, an intermediate progenitor cell, was increased in cerebral cortex of VDD-fed fetuses. Moreover, DKK1, a WNT/β-catenin pathway repressor, was elevated in cerebral cortex of VDD-fed fetuses. By contrast, β-catenin, a critical effector of the WNT/β-catenin pathway, was reduced in cerebral cortex of GD14 VDD fetuses. These results provide partial evidence that maternal vitamin D deficiency during pregnancy and lactation induces autism-like behaviors partly by suppressing WNT/β-catenin pathway in the cerebral cortex.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112737"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097225","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":"Glial activation and increased blood brain barrier permeability in the medial preoptic area of male mice lacking neural androgen receptor","authors":"Nida Karameh ,&nbsp;Afnan Atallah ,&nbsp;Danaé Nuzzaci ,&nbsp;Valérie Grange-Messent ,&nbsp;Sakina Mhaouty-Kodja","doi":"10.1016/j.mce.2026.112742","DOIUrl":"10.1016/j.mce.2026.112742","url":null,"abstract":"<div><div>We have previously shown that testosterone depletion in adult male mice induced neural androgen receptor (<em>Ar</em>) down-regulation and led to neuroinflammation and increased blood brain barrier (BBB) permeability in the medial preoptic area. In the present study, we investigated the effects of neural <em>Ar</em> deletion on glial function and BBB integrity in male mice. For this purpose, we used control and mutant littermates obtained from a mouse line deleted for the <em>Ar</em> in neural progenitors by Cre-loxP technology. Neural <em>Ar</em> deletion induced glial activation evidenced by increased immunoreactivity against markers of astrocytes (glial fibrillary acidic protein -GFAP- and N-myc downstream-regulated gene 2) and microglia (ionized calcium binding adaptor molecule 1). Fluoro-Jade® C fluorescent labeling was increased and inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) were detected in the vicinity of capillaries in the male medial preoptic area of neural <em>Ar</em> knockout mice. Analysis of BBB integrity showed enhanced permeability for Evans Blue tracer and endogenous immunoglobulins in mutant animals compared to their control littermates. In addition, modifications in the ultrastructural organization of capillary endothelial tight junctions were observed by electron tomography. These effects were specific to neural <em>Ar</em> deletion since no changes were observed for GFAP-immunoreactivity, BBB permeability or Fluoro-Jade® C labeling in male mice expressing the wild type <em>Ar</em> allele and carrying the Cre transgene.</div><div>Altogether, these data indicate the key role of the neural AR in testosterone-induced regulation of astrocyte, microglial and BBB functions in the medial preoptic area of male mice.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112742"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049005","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":"HIF-2α expression is controlled by the progesterone receptor and regulates hCG-induced gene expression in granulosa cells during ovulation in mice","authors":"Alison E. Roennfeldt ,&nbsp;Doan T. Dinh ,&nbsp;Timothy R. McPhee ,&nbsp;Ryan D. Rose ,&nbsp;Kirsten M. Smith ,&nbsp;Minnu Jayapal ,&nbsp;Timothy P. Allen ,&nbsp;Rebecca L. Robker ,&nbsp;David C. Bersten ,&nbsp;Daniel J. Peet ,&nbsp;Darryl L. Russell","doi":"10.1016/j.mce.2026.112754","DOIUrl":"10.1016/j.mce.2026.112754","url":null,"abstract":"<div><div>Ovulation is induced via a surge in gonadotrophin hormones, which increases the expression of the essential ovulatory transcription factor progesterone receptor (PGR) and its target genes. The importance of PGR in ovulation is well defined; however, the role of its many downstream genes largely remains unknown. Using mouse models of ovulation, we show that the <em>Epas1</em> gene, which encodes the hypoxia inducible transcription factor 2α (HIF-2α), is expressed in a PGR-dependent manner during ovulation. Numerous HIF target genes increase in expression upon gonadotrophin stimulation in mouse granulosa cells, with expression of <em>Epas1,</em> but not its related isoform, <em>Hif1a,</em> increasing in a PGR-dependent manner. PGR directly binds introns of the <em>Epas1</em> locus to enhance chromatin accessibility in ovarian granulosa cells <em>in vivo,</em> yet no evidence of PGR-dependent <em>Epas1</em> expression was observed in PGR-expressing breast cancer cell lines, suggesting ovary-specific mechanisms of PGR-dependent <em>Epas1</em> regulation. PGR activation in response to hormonal stimulation induced expression of a HIF reporter system in primary human granulosa cells, with HIF-2 inhibition with the small molecule PT-2385 confirming a HIF-2 contribution to this response. Upon HIF-2 inhibition with PT-2385 in mice, no change in ovulation counts were observed. However, gonadotrophin-induced ovary gene expression was significantly disrupted, supporting a model where HIF-2α contributes to the control of periovulatory gene expression downstream of PGR. In particular, inflammatory gene expression was dysregulated and a cohort of gonadotrophin-dependent genes, including <em>Pgr</em>, were elevated, suggesting impaired downregulation post-ovulation. These findings provide an important insight into regulation of the hypoxia inducible transcription factors during ovulation and how targeting HIF-2α may be of benefit in future fertility treatments.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112754"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125624","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}