Frontiers in Cell and Developmental Biology最新文献

{"title":"Epicardium-myocardium crosstalk orchestrates heart development.","authors":"Anika Nusrat, Mingfu Wu","doi":"10.3389/fcell.2025.1655878","DOIUrl":"10.3389/fcell.2025.1655878","url":null,"abstract":"<p><p>The epicardium is critical in heart development, functioning as a paracrine signaling hub and a source of progenitor cells. Bidirectional communication between the epicardium and myocardium, mediated by tightly regulated signaling networks, is essential for proper cardiac morphogenesis. This review presents a comprehensive overview of epicardium-myocardium crosstalk across species, emphasizing how this crosstalk influences epicardial epithelial-to-mesenchymal transition (EMT), fate specification of epicardium-derived cells (EPDCs), myocardial proliferation and growth, and coronary vasculature development. We critically assess decades of research elucidating key pathways-retinoic acid, fibroblast growth factor (Fgf), insulin-like growth factor (Igf), platelet-derived growth factor (Pdgf), transforming growth factor-β (Tgfβ), various transcriptional and epigenetic regulators, as well as calcium signaling mediated epicardial function-that coordinate these developmental processes. Additionally, we include detailed tables summarizing key experimental models and mechanistic insights that have shaped the field. This integrative analysis advances our current understanding of epicardial-myocardial crosstalk and highlights unresolved questions to guide future investigations into cardiac development and disease.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1655878"},"PeriodicalIF":4.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic state and female fertility in ART cycles: a summary of current advances.","authors":"Natascha Berger, Katharina Brugger, Herbert Fluhr","doi":"10.3389/fcell.2025.1645127","DOIUrl":"10.3389/fcell.2025.1645127","url":null,"abstract":"<p><p>This mini review explores the evolving landscape of metabolic disturbances and their impact on female reproductive outcomes, with a particular focus on emerging molecular biomarkers and novel metabolic phenotypes. Metabolic health plays a pivotal role in female reproductive function, with well-established endocrine-metabolic disorders, such as polycystic ovary syndrome, obesity, and diabetes mellitus, known to impair fertility. This review explores these conditions, including less commonly studied phenotypes like normal weight obesity, metabolically obese normal weight, and metabolically healthy obesity, which challenge traditional diagnostic frameworks by presenting metabolic risk independent of body mass index. These underrecognized profiles can adversely affect ovarian physiology, endometrial receptivity, and assisted reproductive technology outcomes. The review further highlights potential biomarkers, including bile acids and advanced glycation end-products, as promising diagnostic and therapeutic targets. By integrating insights from metabolic regulation, endocrinology, and reproductive biology, this article emphasizes the need for a more nuanced, individualized approach to fertility assessment and treatment. Understanding these interconnections is vital for advancing personalized medicine, particularly in addressing unexplained infertility and optimizing assisted reproductive technology success.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1645127"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of metabolic biomarkers in renal cell carcinoma: from molecular mechanisms to clinical implications.","authors":"Junkai Yang, Daojia Miao, Xinwei Li, Chuanyi Zhao, Diaoyi Tan, Songming Wu, Feiyi Lu, Jian Shi, Qingyang Lv, Hailong Ruan, Zhiyong Xiong, Xiaoping Zhang","doi":"10.3389/fcell.2025.1664292","DOIUrl":"10.3389/fcell.2025.1664292","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) is a common malignancy of the urinary system. Due to its asymptomatic nature in the early stages, many patients present with advanced or metastatic disease at the time of diagnosis. Existing therapeutic strategies for advanced RCC exhibit limited efficacy, underscoring the urgent need for novel therapeutic approaches. Recently, metabolic reprogramming-characterized by alterations in glucose metabolism, lipid synthesis, and amino acid metabolism-has emerged as a critical biological adaptation enabling tumor cell proliferation and survival within the tumor microenvironment. This review introduces the major metabolic reprogramming mechanisms in RCC, including enhanced glycolysis, augmented lipid synthesis, and altered amino acid metabolism. We summarize the associations between RCC progression and key metabolic molecules involved in these pathways, highlighting their potential clinical value as diagnostic markers, prognostic indicators, and therapeutic targets. To date, most studies have focused primarily on describing the correlations between metabolic dysregulation and tumor progression or therapeutic resistance in RCC. However, the molecules and pathways involved in these metabolic processes also represent promising targets for metabolic interventions. In this context, we further propose novel therapeutic strategies targeting key metabolic nodes such as HIF-2α, GLUT and FASN, offering new insights into precision treatment approaches for RCC.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1664292"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoration of skeletal muscle function via mesenchymal stem cells: mechanistic insights and therapeutic advances in myasthenia gravis.","authors":"Xinyi Zhang, Dongmei Zhang, Ying Zhang, Jian Wang, Jing Lu","doi":"10.3389/fcell.2025.1658062","DOIUrl":"10.3389/fcell.2025.1658062","url":null,"abstract":"<p><p>Mesenchymal stem cells (MSCs) have demonstrated distinct advantages in skeletal muscle repair owing to their self-renewal capacity, multidirectional differentiation potential, and immunomodulatory functions. As a critical regulator of skeletal muscle regeneration, MSCs have been shown to ameliorate skeletal muscle injury induced by factors such as wasting and metabolic disorders through the activation of satellite cell function, inhibition of myofiber atrophy, and regulation of protein metabolic balance. In the treatment of myasthenia gravis (MG), the therapeutic effects of MSCs are exerted through dual mechanisms: first, autoantibody production is reduced via immunomodulation, thereby alleviating immune-mediated attacks at neuromuscular junctions; second, secondary muscle atrophy is delayed by preserving the integrity of neuromuscular signaling. Notably, MSC function is closely associated with acetylcholine metabolism, neuromuscular junction stability, and the aging microenvironment, in which aging-induced MSC decline may exacerbate intramuscular fat infiltration and impair regenerative capacity. In this paper, the biological properties of mesenchymal stem cells (MSCs) and their regulatory roles in skeletal muscle metabolic and injury-related abnormalities are systematically reviewed, and the fundamental significance of MSCs in skeletal muscle repair and myasthenia gravis (MG) therapy is elucidated through multiple mechanisms, including immunomodulation, neuroprotection, and muscle fiber regeneration. Furthermore, the bottlenecks of clinical translation (including cell source selection, phenotypic stability, and efficacy heterogeneity) are analyzed, and the challenges and optimization strategies for clinical application are discussed, with the aim of providing theoretical references for regenerative medicine research in neuromuscular diseases. However, clinical translation studies have indicated that the actual efficacy of most MSC-based therapies is considerably lower than that observed in <i>in vitro</i> experiments. This discrepancy may be attributed to low post-transplantation cell survival, inadequate homing efficiency, and the adverse influence of a senescent microenvironment that impairs cellular function. It has been indicated by recent studies that strategies, including optimization of cell sources and preparation protocols (e.g., the use of allogeneic MSCs derived from adipose tissue or umbilical cord with standardized production), incorporation of biomaterial supports (such as hydrogel-based encapsulation), and adoption of combination therapies (e.g., co-administration with neurotrophic factors or targeted drugs), can effectively improve the delivery efficiency and therapeutic outcomes of MSCs.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1658062"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6 trans-signaling in cystic fibrosis bronchial cells potentiates TNF-α-driven ICAM-1 expression.","authors":"John Lin, Lyvia Fourcade, Lucie Roussel, Matthew Marabella, Julie Bérubé, Dao Nguyen, Simon Rousseau","doi":"10.3389/fcell.2025.1566482","DOIUrl":"10.3389/fcell.2025.1566482","url":null,"abstract":"<p><strong>Introduction: </strong><i>Pseudomonas aeruginosa</i> is gram-negative <i>bacillus</i> that causes chronic airway infections, leading to severe pulmonary inflammation in cystic fibrosis. This bacterial infection is frequently associated with a massive recruitment of neutrophils and an abnormal increase in production of inflammatory cytokines. Among these cytokines, interleukin (IL)-6 has both anti- and pro-inflammatory properties able to signal through classic and trans-signaling pathways, respectively. Furthermore, IL-6 is known to be upregulated in CFTR-deficient bronchial cell lines in the presence of <i>Pseudomonas aeruginosa</i>-derived filtrates and in Pulmonary Exacerbations (PEx). In this study, we aimed to determine whether IL-6 trans-signaling could contribute to neutrophilic inflammation leading to lung tissue damage during PEx of people with CF (pwCF).</p><p><strong>Methods: </strong>sIL-6Ra expression was measured by ELISA in plasma samples from pwCF at baseline and during exacerbations. IL-6 signalling was investigate in CF and non-CF cell lines using immunoblotting of STAT3 phosphorylation. ICAM-1 cell surface expression was determined using flow cytometry.</p><p><strong>Results: </strong>We show that pwCF had higher sIL-6Rα levels in their plasma during PEx, suggestive of IL-6 trans-signaling. Furthermore, we show that a CF bronchial cell line is hyper-responsive to both classic and trans-signaling, with the higher levels of activation occurring during trans-signaling when compared to two non-CF cell lines.</p><p><strong>Discussion: </strong>Our data unveiled that ICAM-1, which promotes neutrophil adhesion, is upregulated by the combination of TNF-α and IL-6 signaling in CF bronchial cells. Interestingly, soluble IL-6R (sIL-6Rα) protects IL-6 from degradation by bacterial proteases. Therefore, we suggest that strategies which target IL-6 trans-signaling may alleviate ICAM-1 mediated neutrophil adhesion and reduce subsequent lung damage in PEx.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1566482"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Editorial: Mechanisms of microenvironment governed plasticity and progression in solid tumors.","authors":"Jonathan A Kelber, Marcin Iwanicki, Marianna Kruithof-de Julio, Benjamin T Spike, Michelle M Martínez-Montemayor","doi":"10.3389/fcell.2025.1702303","DOIUrl":"https://doi.org/10.3389/fcell.2025.1702303","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fcell.2024.1373496.].</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1702303"},"PeriodicalIF":4.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nomogram for predicting pathological complete response to neoadjuvant chemoimmunotherapy in patients with resectable non-small cell lung cancer.","authors":"Wenyi Liu, Zhilin Sui, Chunguang Wang, Youjun Deng, Songhua Cai, Ran Jia, Zhentao Yu, Mingqiang Kang, Baihua Zhang","doi":"10.3389/fcell.2025.1679782","DOIUrl":"10.3389/fcell.2025.1679782","url":null,"abstract":"<p><strong>Objectives: </strong>Neoadjuvant chemoimmunotherapy is increasingly employed in resectable non-small cell lung cancer (NSCLC), with variable pathological complete response (pCR) rates. Currently, no reliable preoperative tool is available for predicting pCR. This study develops a nomogram based on clinical variables to predict pCR and guide individualized surgical decisions.</p><p><strong>Methods: </strong>We retrospectively analyzed data from 179 NSCLC patients (stages IIB-IIIB) who received neoadjuvant chemoimmunotherapy followed by resection (2019-2022). Variables included demographics, smoking history, comorbidities, treatment details, and pathology. Univariate and multivariate logistic regression identified pCR predictors, which were incorporated to build a nomogram. Performance was assessed via area under the curve (AUC), calibration, and decision curve analysis (DCA).</p><p><strong>Results: </strong>Of 179 patients, 92 (51.4%) achieved pCR. Multivariate analysis identified independent predictors: non-squamous histology (OR 0.344 (non-squamous vs. squamous), 95% CI 0.151-0.707, p = 0.006), positive family history (OR 10.76 (positive vs. negative), 95% CI 1.903-203.3, p = 0.027), shorter smoking cessation duration (defined as time in days from last cigarette to treatment start) (OR 0.999 (per day), 95% CI 0.999-0.999, p = 0.033), older age (OR 1.053 (per year), 95% CI 1.005-1.106, p = 0.032), and more treatment cycles (OR 1.621 (per cycle), 95% CI 1.007-2.661, p = 0.049). The nomogram showed modest discrimination (AUC 0.709, 95% CI 0.633-0.785), good calibration, and net benefit on DCA, though it has not been externally validated and is limited by single-center data, small sample size, high pCR rate, and skewed demographics (95.5% male, 92.7% smokers), potentially limiting generalizability to diverse populations such as females or non-smokers.</p><p><strong>Conclusion: </strong>This nomogram, derived from routine clinical data, predicts pCR after neoadjuvant chemoimmunotherapy in NSCLC, offering a tool for thoracic surgeons to optimize treatment and surgical planning, despite its modest discriminative power, by serving as a complementary aid in resource-limited settings where biomarkers may not be readily available. External validation in larger, multi-center cohorts is essential.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1679782"},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Posttranslational microtubule modification alters podocalyxin-trafficking in epithelial cells.","authors":"Lena-Sophie Gorek, Dominik Trauth, Natalia Kamm, Lana Sophie Schiffke, Carlotta Zerbian, Lina-Marie Mende, Ralf Jacob","doi":"10.3389/fcell.2025.1667313","DOIUrl":"10.3389/fcell.2025.1667313","url":null,"abstract":"<p><p>Epithelial polarization is characterized by separation of the plasma membrane into an apical and a basolateral membrane domain. This morphology is verified by cytoskeletal organization that stabilizes the cellular architecture and provides specific tracks for correct polarized cargo delivery. Here, we studied effects of tubulin (de-) tyrosination on epithelial polarization and apical trafficking of the membrane protein podocalyxin/gp135. Therefore, tubulin tyrosine ligase (TTL), the enzyme that adds tyrosine to the carboxy terminus of detyrosinated α-tubulin, was knocked out or overexpressed in MDCK cells. TTL-knockout alters podocalyxin-expression and -glycosylation, which was compensated by overexpression or rescue of TTL. Moreover, intracellular interaction of podocalyxin with ezrin was reduced in the absence of TTL. This suggests that posttranslational microtubule-modification can modulate maturation and function of the glycoprotein. We used the SNAP-tag system to examine membrane delivery of podocalyxin and found atypical spreading of the newly synthesized glycoprotein all over the apical membrane and an altered subapical architecture of microtubules in cells with an elevated content of detyrosinated α-tubulin. Our studies suggest that intracellular trafficking of podocalyxin can be controlled by TTL-dependent posttranslational modification of microtubules in polarized epithelial cells.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1667313"},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FRA1 (<i>FOSL1</i>) suppresses neoplastic transformation and modulates radiation responses via transcriptional control of mitogenic and stress-responsive networks.","authors":"Wuroud Al-Khayyat, Taylor Laframboise, Jessica Dougherty, Marc S Mendonca, Douglas R Boreham, T C Tai, Christopher Thome, Sujeenthar Tharmalingam","doi":"10.3389/fcell.2025.1659986","DOIUrl":"10.3389/fcell.2025.1659986","url":null,"abstract":"<p><strong>Purpose: </strong>FOS-like antigen 1 (FRA1), encoded by <i>FOSL1</i>, is an inducible subunit of the AP-1 transcription factor complex and regulates gene expression in response to proliferative and environmental cues. Although FRA1 has been linked to cancer progression, its role in early transformation and radiation responses remains unclear.</p><p><strong>Methods: </strong>CRISPR-engineered human CGL1 cells-a hybrid of HeLa and normal fibroblasts-were used to evaluate the impact of FRA1 overexpression and knockout on neoplastic transformation. Transformation frequency, clonogenic survival, DNA damage recognition and repair, and cell cycle distribution were assessed following irradiation. Transcriptomic profiling was performed under baseline and serum-stimulated conditions.</p><p><strong>Results: </strong>FRA1 loss markedly increased both spontaneous and radiation-induced transformation frequency, while overexpression suppressed transformation under both conditions. FRA1-deficient cells were sensitized to radiation-induced cell killing, despite intact DNA damage recognition and repair. In contrast, FRA1 overexpression promoted G2/M accumulation post-irradiation, suggesting enhanced checkpoint activation. Transcriptomic profiling revealed that FRA1 remodels AP-1 complex composition and functions as a transcriptional repressor of mitogen- and stress-responsive genes. FRA1-mediated repression was observed across gene networks involved in extracellular matrix remodeling, hypoxia signaling, inflammation, and proliferation, under both baseline and serum-stimulated conditions.</p><p><strong>Conclusion: </strong>These findings establish FRA1 as a key modulator of neoplastic transformation and radiation response, acting primarily through transcriptional repression of pro-tumorigenic signaling pathways.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1659986"},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excessive progesterone impairs mouse decidualization via the Kyn-AhR pathway.","authors":"Hui-Na Luo, Hong-Yuan Yang, Zai-Mei Wang, Jia-Mei Luo, Tong-Tong Zhang, Zeng-Ming Yang","doi":"10.3389/fcell.2025.1622998","DOIUrl":"10.3389/fcell.2025.1622998","url":null,"abstract":"<p><p>Progesterone (P₄) is essential for pregnancy establishment and maintenance. Clinically, P₄ is widely used to regulate the menstrual cycle, maintain pregnancy, and treat luteal phase deficiency. However, P₄ administration protocols, particularly regarding routes, dosage, and timing remain poorly defined. Although excessive P₄ impairs embryo implantation and decidualization in mice, the underlying mechanism remains unclear. Our data show that decidualization in day 8 pregnant mice and artificial decidualization in day 8 pseudopregnant mice are impaired by 4 mg or 8 mg/mouse P₄. The mRNA levels of <i>Prl8a2 and Prl3c1,</i> markers of <i>in vitro</i> decidualization are significantly downregulated by 10 or 20 μM P₄. The uterine fluorescent signal of indoleamine 2,3-dioxygenase 1 (IDO1) and protein levels of tryptophan 2,3-dioxygenase (TDO) are increased after ovariectomized mice are treated with excessive P₄. Treatment of uterine stromal cells with excessive P₄ also significantly upregulates the protein levels of IDO1 and TDO, and kynurenine (Kyn) secretion. Epacadostat (IDO1 antagonist) or RU486 (progesterone receptor antagonist) effectively block P₄-induced Kyn elevation. The mRNA levels of <i>Prl8a2</i> and <i>Prl3c1 and</i> the protein levels of BMP2 are significantly inhibited by Kyn. The high-dose of P₄ activates the aryl hydrocarbon receptor (AhR) and its downstream targets CYP1A1 and CYP1B1. Under <i>in vitro</i> decidualization, the mRNA levels of <i>Prl8a2</i> and <i>Prl3c1</i> are inhibited by 2-OH-E₂ and 4-OH-E₂, the catalytic products of CYP1A1 and CYP1B1, respectively. CH-223191, a specific AhR antagonist, effectively counteracts the effects of Kyn on <i>Cyp1a1</i>, <i>Cyp1b1</i>, and <i>Prl8a2</i> expression. Additionally, nucleolar size in stromal cells is increased both <i>in vivo</i> and <i>in vitro</i> following excessive P₄ treatment. Our findings suggest that excessive P₄ impairs mouse decidualization via the Kyn-AhR pathway.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1622998"},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}