Frontiers in Cell and Developmental Biology最新文献

{"title":"CNOT6L regulates energy metabolism in the ovarian granulosa cells associated with polycystic ovary syndrome.","authors":"Shan Han, Yanqiu Xie, Jiale Lv, Xuedong Sun, Yuhua Shi","doi":"10.3389/fcell.2025.1607161","DOIUrl":"10.3389/fcell.2025.1607161","url":null,"abstract":"<p><p>The endocrine functions exerted by ovarian granulosa cells (GCs) are crucial factors in maintaining follicle development, as oocyte development relies on providing energy substrates and cytokines by ovarian granulosa cells. The mRNA deadenylase level of granulosa cells precisely regulates the follicular development processes. In this study, we detect the expression level of the deadenylase CNOT6L in polycystic ovarian syndrome (PCOS) patients' granulosa cells and mouse models' ovaries. The results found that the CNOT6L significantly upregulated in the ovarian granulosa cells of both PCOS patients and mouse models. Subsequently, we conducted the <i>Cnot6l-</i>overexpressed granulosa cells to explore the alterations by which CNOT6L regulates ovarian granulosa cell function. The overexpression of CNOT6L in granulosa cells significantly inhibited the glycolytic pathway, activated the mitochondrial oxidative phosphorylation pathway, led to a reduction in the generation of the intermediate product lactate, and resulted in impaired energy supply to the oocyte. Subsequently, we performed Full-length transcriptome sequencing on the granulosa cells and investigated the impact of mRNA poly(A) level differences on granulosa cell dysfunction in PCOS. This study offers new insights into the role of CNOT6L in regulating energy metabolism homeostasis and its involvement in follicular developmental disorders related to polycystic ovary syndrome.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1607161"},"PeriodicalIF":4.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208184","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":"Nodal and cripto-1: distinct functions regulate trophoblast specification in mouse pregnancy.","authors":"Laura Girardet, Neha Kamath, Daniel Dufort","doi":"10.3389/fcell.2025.1608976","DOIUrl":"10.3389/fcell.2025.1608976","url":null,"abstract":"<p><strong>Introduction: </strong>Proper placentation is essential for fetal growth and development in mammals. Nodal signaling is essential to ensure proper embryo development and requires Cripto-1 as a co-receptor. Both factors have been shown to be expressed in the maternal decidua and developing placenta. Notably, a maternal loss of either Nodal or Cripto-1 leads to defective placentation resulting in intrauterine growth restriction and fetal loss. However, the role of Nodal or Cripto-1 in placental development has not been determined.</p><p><strong>Methods: </strong>To better understand the roles of Nodal and Cripto-1 in trophoblast populations, we employed a trophoblast-specific deletion model using Tat-Cre recombinant protein to induce deletion of the floxed Nodal or Cripto-1 genes exclusively in the trophectoderm at the blastocyst stage (TE-KO). Treated embryos were then transferred into the uteri of pseudopregnant mice, and implantation sites were examined at gestational days (d) 8.5 and 10.5. Placental morphology and trophoblast populations were analyzed through histological and molecular marker analysis.</p><p><strong>Results: </strong>TE-KO of Nodal led to a decrease in the implantation site size and placental thickness, primarily due to a smaller labyrinth area while the junctional zone was increased. Immunostaining revealed an important expansion of PL⁺ trophoblast giant cells and decrease of TPBPA⁺ spongiotrophoblast/glycogen cells. TE-KO of Cripto-1 also led to smaller implantation sites and reduced placental thickness, but this was attributed to a smaller junctional zone. A decrease in TPBPA⁺ spongiotrophoblast cells without affecting <i>Pcdh12</i> ⁺ glycogen cells was observed. A reduction in MCT1⁺ and <i>Gcm1</i> ⁺ syncytiotrophoblasts and an increase in total area of maternal blood sinuses within the labyrinth emphasized its disorganization. Earlier effects of Cripto-1 TE-KO on the trophoblast maintenance were witnessed at d8.5, with a marked reduction in TPBPA⁺ cells, reduced trophoblast cell proliferation (PCNA⁺) and increased apoptosis (TUNEL⁺).</p><p><strong>Discussion: </strong>The distinct phenotypes observed indicate the different roles Nodal and Cripto-1 play in placental development. This highlights the importance of other TGF-β-dependent and independent pathways involving Cripto-1. Overall, our findings highlight the critical role of Nodal and Cripto-1 in regulating key aspects of placental development, including trophoblast differentiation, cellular specification, and structural organization, promising avenues for future research in placental biology.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1608976"},"PeriodicalIF":4.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208186","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":"Comprehensive analyses of telomerase component DKC1 and its association with clinical, molecular and immune landscapes in uterine corpus endometrial carcinoma.","authors":"Chenxi Sun, Xu Liu, Tiantian Liu, Chenliu Fan, Yang Jiang, Binggen Li, Huiyang Yuan, Chengyun Zheng, Dawei Xu","doi":"10.3389/fcell.2025.1592135","DOIUrl":"10.3389/fcell.2025.1592135","url":null,"abstract":"<p><strong>Background: </strong>Telomerase activation is essential to malignant transformation and progression including uterine corpus endometrial carcinoma (UCEC), while telomerase co-factor DKC1-mediated RNA pseudouridylation is required for functional telomerase by stabilizing telomerase RNA component (TERC) and its upregulation occurs in many cancers. Surprisingly, there is only one publication studying DKC1 in UCEC, which shows its significant downregulation.</p><p><strong>Objective: </strong>DKC1 expression, its role in the UCEC molecular pathogenesis and clinical implications were comprehensively investigated.</p><p><strong>Methods: </strong>Thirty UCEC patients were recruited to determine DKC1 expression in both tumors and non-tumorous endometrial tissues (NT) using immunohistochemistry. Four UCEC cohorts from TCGA and GSE datasets were analyzed for DKC1 expression and its impacts on clinic-pathological, molecular, genomic and immune landscapes.</p><p><strong>Results: </strong>Immunohistochemistry analyses showed significantly increased DKC1 expression in UCEC tumors than in NTs and its highest level was observed in high-grade tumors. For the TCGA cohort, DKC1 mRNA and protein levels increased significantly in tumors compared with that in NTs. DKC1 mRNA levels positively correlated with TERC and telomerase activity. Higher DKC1 expression predicted shorter patient overall and progression-free survival. DKC1 copy number alterations were frequent in UCEC tumors. Estrogen treatment of UCEC cells upregulated DKC1 expression while medroxyprogesterone inhibited its expression. DKC1-high UCEC tumors exhibited hyperproliferation, increased stemness and epithelial-mesenchymal transition, accompanied by significantly higher aneuploid, homologous recombination deficiency and micro-satellite instable scores, and higher frequencies of cancer driver aberrations. Lower immune scores were observed in DKC1-high tumors as assessed by ESTIMATE algorithm. Tumor Immune Dysfunction and Exclusion (TIDE) analyses revealed robustly higher TIDE scores featured with T Cell exclusion in DKC1-high tumors, and consistently, the diminished trafficking of immune cells into tumor tissues and substantial declines in immune cell infiltration were shown in these tumors. Moreover, DKC1-high tumors exhibited poor response to immune checkpoint inhibitor (ICI)-based immunotherapy. These observations were validated by the findings obtained from other datasets.</p><p><strong>Conclusion: </strong>The present findings unravel genomic alteration- and sex hormone-mediated dysregulation of the telomerase cofactor DKC1 in UCEC tumors, and its upregulation participates actively in the UCEC pathogenesis through tumor-intrinsic and extrinsic mechanisms. DKC1 assessment is useful for patient prognostication and personalized interventions.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1592135"},"PeriodicalIF":4.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12127311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208185","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":"Transcorneal electrical stimulation: impact on healthcare and future potential.","authors":"Takeshi Morimoto","doi":"10.3389/fcell.2025.1569759","DOIUrl":"10.3389/fcell.2025.1569759","url":null,"abstract":"<p><p>Transcorneal electrical stimulation (TES), a noninvasive therapeutic technique, has gained attention for its potential to treat retinal and optic nerve diseases. TES involves applying weak electrical currents via electrodes on the cornea to stimulate retinal ganglion cells (RGCs) without causing activation of photoreceptors, inducing phosphenes, and enabling the evaluation of inner retinal function. This is valuable for assessing residual retinal activity in patients with photoreceptor or RGC degeneration. Furthermore, TES has shown significant neuroprotective effects on RGCs and photoreceptors through mechanisms involving the upregulation of neurotrophic factors (e.g., insulin-like growth factor 1, brain-derived neurotrophic factor, and ciliary neurotrophic factor), reduction of inflammatory responses, and enhanced ocular blood flow. These findings are supported by extensive animal studies, showing its efficacy in mitigating retinal degeneration and optic nerve damage while promoting axonal regeneration. Clinically, TES has shown potential in improving visual function in diseases such as RP, optic neuropathies, and ischemic retinal conditions; however long-term benefits remain a challenge. Randomized controlled trials have indicated the safety and modest therapeutic effects of TES, suggesting its potential as an adjunct treatment for visual impairments. Moreover, TES may extend beyond ophthalmology into neurology. Because the retina is anatomically connected to the brain, TES can influence brain regions such as the visual cortex and hippocampus. Preliminary research proposes its potential for modulating brain, such as those with retinitis pigmentosa (RP). TES has demonstrated significant neuroprotective effects in networks, cognition, and emotional pathways, offering hope for treating neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In summary, TES represents a versatile and promising therapy for retinal and neurological disorders, and ongoing advancements will likely expand its applications in clinical practice. Further studies are warranted to optimize its parameters, enhance its efficacy, and explore its full therapeutic potential.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1569759"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198707","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":"Comparative analysis of AQP7 expression and cryotolerance in X- and Y-chromosome bearing bovine sperm.","authors":"Jieru Wang, Ruchun Li, Fei Huang, Peng Niu, Yanling Zheng, Dongfang Yuan, Yan Du, Congcong Li, Mingcai Yang, Jiajia Suo, Qinghua Gao","doi":"10.3389/fcell.2025.1582961","DOIUrl":"10.3389/fcell.2025.1582961","url":null,"abstract":"<p><strong>Introduction: </strong>The livestock industry has witnessed a notable increase in the proportion of male calves born following artificial insemination with cryopreserved semen, hinting at a possible association between cryotolerance and inherent structural or functional disparities between X- and Y-chromosome bearing sperm. To delve into this phenomenon, we conducted a comprehensive proteomic analysis on bovine sex-sorted semen.</p><p><strong>Methods: </strong>Sperm samples were meticulously categorized based on stringent quality parameters. Concurrent sorting of X- and Y-sperm from identical ejaculates was performed, followed by protein extraction for subsequent analysis. Quantitative isobaric tags for relative and absolute quantification (iTRAQ) were employed to identify differentially expressed proteins.</p><p><strong>Results: </strong>iTRAQ pinpointed 20 proteins with differential expression between X- and Y-spermatozoa, including 12 upregulated and 8 downregulated proteins in Y-sperm. Aquaporin 7 (AQP7), significantly upregulated in Y-sperm, was identified as a key candidate. Western blot analysis corroborated elevated AQP7 expression in Y-sperm compared to X-sperm, while Aquaporin 3 (AQP3) showed no significant difference. Immunofluorescence revealed AQP7 localization to the post-acrosomal region, midpiece, and principal piece of Y-sperm with higher fluorescence intensity, whereas AQP3 distribution was comparable between groups.</p><p><strong>Discussion: </strong>These findings imply a potential role for AQP7 in augmenting Y-sperm cryotolerance, providing molecular insights into sex-specific cryopreservation effects on fertility outcomes. Future research should elucidate AQP7's functional mechanisms and explore implications for livestock breeding technologies.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1582961"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198691","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":"Optimal Sca-1-based procedure for purifying mouse adipose-derived mesenchymal stem cells with enhanced proliferative and differentiation potential.","authors":"Xingyu Tao, Jialian Wang, Yuan Yan, Peifeng Cheng, Bin Liu, Huimin Du, Bailin Niu","doi":"10.3389/fcell.2025.1566670","DOIUrl":"10.3389/fcell.2025.1566670","url":null,"abstract":"<p><strong>Introduction: </strong>Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for mesenchymal stem cell (MSC) therapy due to their ease of isolation from the stromal vascular fraction (SVF) of adipose tissue. However, traditional isolation methods often result in mouse ADSCs with low purity and significant heterogeneity contributing to inconsistencies in results from preclinical and clinical studies. This is partly attributed to the lack of consensus on their surface markers.</p><p><strong>Methods: </strong>This study compared three purification methods for isolating mouse ADSCs based on Sca-1 positivity-direct adherence (ADSC-A), magnetic cell sorting followed by adherence (ADSC-M), and adherence to the third generation followed by magnetic cell sorting (ADSC-AM). Third-generation ADSCs were evaluated for proliferative activity, differentiation potential, and functional enrichment using proliferation assays, trilineage differentiation assays, and RNA sequencing. Flow cytometry was employed to assess Sca-1 positivity and the expression of positive (CD44, CD90, CD29) and negative markers (CD31, CD45) in the fourth-generation ADSCs.</p><p><strong>Results: </strong>Among the three methods, ADSC-AM exhibited superior properties, including uniform morphology, enhanced proliferation, and over 95% expression of Sca-1 and CD29. While all methods supported trilineage differentiation, ADSC-AM demonstrated enhanced adipogenesis. Furthermore, RNA sequencing and pathway enrichment analysis revealed that ADSC-AM possessed unique potential in angiogenesis and immune regulation.</p><p><strong>Discussion: </strong>These findings suggest that the ADSC-AM method offers a simple and reproducible approach for obtaining high-purity mouse ADSCs with better functional properties and provide a fundamental reference for understanding mouse ADSCs surface marker profiles.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1566670"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198693","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":"Editorial: Senescence and reprogramming: hallmarks in aging and disease.","authors":"F Javier González-Rico, Jiyue Zhu, Guangyong Peng","doi":"10.3389/fcell.2025.1622682","DOIUrl":"10.3389/fcell.2025.1622682","url":null,"abstract":"","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1622682"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198692","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":"The role of IGF-2 and its variants in enhancing endothelial migration and angiogenesis.","authors":"Lotte Alders, Elke Pirlet, Emma Gesquiere, Annelies Bronckaers","doi":"10.3389/fcell.2025.1598705","DOIUrl":"10.3389/fcell.2025.1598705","url":null,"abstract":"<p><strong>Introduction: </strong>Angiogenesis, the formation of new blood vessels, is essential for physiological processes such as tissue repair as well as pathological conditions including cancer. While insulin-like growth factor 2 (IGF-2) is identified as a key regulator of angiogenesis, the contributions of its variants remain less explored.</p><p><strong>Methods: </strong>We compared the effects of wildtype IGF-2 with that of Des(1-6)IGF-2, which has lower affinity to IGF-binding proteins (IGFBPs), and Leu27IGF2, which interacts selectively with the IGF-Receptor 2. We analyzed their effect on endothelial cell migration and tube formation as well as on the secretome of endothelial cells using an antibody array. In addition, the regulatory influence of IGF-binding protein 6 (IGFBP-6) in modulating these effects was investigated. Finally, the ability of the three different variants of IGF-2 to induce blood vessel formation was studied using the chicken 'chorioallantoic membrane' (CAM) assay.</p><p><strong>Results: </strong>IGF-2 and Des(1-6)IGF-2 significantly promoted endothelial cell migration and tube formation <i>in vitro</i>, while also increasing blood vessel formation <i>in ovo</i>. An angiogenesis antibody array revealed that these effects were mediated through the upregulation of several angiogenic proteins, including IL-6, uPAR, and MCP-1. Interestingly, Leu27IGF-2 exhibited a weaker effect, suggesting that IGF receptor 1 and/or insulin receptor activation plays a major role in these processes. IGFBP-6 effectively inhibits IGF-2-induced effects but has no impact on Des(1-6)IGF-2, highlighting the latter's ability to evade IGFBP-mediated inhibition due to structural modifications.</p><p><strong>Conclusion: </strong>These results suggest that Des(1-6)IGF-2 may serve as a potent pro-angiogenic agent with therapeutic potential, while IGFBP-6 could offer a strategy for suppressing pathological angiogenesis.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1598705"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198695","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":"Immunolocalization and proteomic analyses of IZUMO1 in porcine spermatozoa.","authors":"Miranda Hernández-Falcó, Paula Sáez-Espinosa, Andrea López-Botella, Laura Robles-Gómez, Francisco Alberto García-Vázquez, Maria José Izquierdo-Rico, Pedro José Llamas-López, María José Gómez-Torres","doi":"10.3389/fcell.2025.1576881","DOIUrl":"10.3389/fcell.2025.1576881","url":null,"abstract":"<p><p>Reproduction is fundamental to breeding programs aimed at increasing productivity in swine industry. However, the application of <i>in vitro</i> embryo production in this species is limited because of the polyspermy. Therefore, characterizing proteins involved in sperm-oocyte binding such as IZUMO1 becomes essential. This study aimed to characterize porcine IZUMO1 protein under three different physiological states: sperm-rich fraction (SRF), 1-h capacitated sperm selected by <i>swim-up</i> (CS), and induced acrosome reaction in 1-h capacitated sperm (ARS). The immunolocalization of IZUMO1 and acrosome status of fifteen fertile boars was assessed by confocal microscopy. Additionally, six males were subjected to a more detailed examination via quantitative proteomic analysis by LC-MS/MS. Fluorescence results revealed four distinct IZUMO1 distribution patterns: pattern 1 (P1) characterized by speckled staining in the pre-equatorial subdomain and postacrosomal domain, pattern 2 (P2) displaying strong apical ridge staining with speckled staining in the pre-equatorial subdomain and postacrosomal domain, pattern 3 (P3) exhibiting speckled staining in the postacrosomal domain, and pattern 4 (P4) without labelling. In the SRF sperm, IZUMO1 was predominantly distributed between staining patterns P1 and P2 (∼50%). As a result of the capacitation, there was a significant decrease in P1. Conversely, in ARS, IZUMO1 was dominantly distributed in P3 51.55% and P4 24.25%. The quantitative study of the IZUMO1 protein supported these findings. With those results and compared with our previous work in human, here we propose a working model of IZUMO1 migration dependent on the morphology and subdomains of the sperm head.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1576881"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224937","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":"The new insight into the role of hydroxyproline in metabolism of cancer cells.","authors":"Magda Chalecka, Justyna Magdalena Hermanowicz, Jerzy Palka, Arkadiusz Surazynski","doi":"10.3389/fcell.2025.1556770","DOIUrl":"10.3389/fcell.2025.1556770","url":null,"abstract":"<p><p>Although the role of proline (Pro) in regulatory mechanisms of cell metabolism is well recognized, the interest in metabolic significance of hydroxyproline (Hyp) has received little attention. Hyp was considered as a waste metabolite of protein degradation, mainly degradation of collagen. This amino acid is not synthesized <i>de novo</i> and is not incorporated into proteins. Hyp is a product of Pro hydroxylation in proteins by specific Pro hydroxylase. Therefore, Hyp is derived from degradation of proteins, and it is further metabolized by specific Hyp dehydrogenase 2 (PRODH2), known also as a Hyp oxidase (OH-POX). The enzyme catalyzes conversion of Hyp into Δ¹-pyrroline-3-OH-5-carboxylic acid (OH-P5C), yielding electrons that are used in electron transport chain for ATP production. However, in certain conditions the electrons are accepted by oxygen forming reactive oxygen species (ROS). The product, OH-P5C could be also converted by OH-P5C reductase to recycle NADP⁺ in pentose phosphate pathway (PPP), yielding nucleotides for DNA synthesis. Interestingly, Pro hydroxylase requires the same cofactors (α-KG, ascorbate and Fe²⁺) as a DNA and histone demethylases, suggesting the role of Pro hydroxylation in epigenetic regulation. Hyp could be also converted to highly energetic amino acid, glycine (Gly). Of great importance is the role of Hyp in upregulation of transcriptional activity of hypoxia-inducible factor 1α (HIF-1α), inducing angiogenesis and metastasis. Therefore, Hyp is involved in several critical metabolic processes regulating DNA synthesis, gene expression, apoptosis/survival, angiogenesis, metastasis and energy production, suggesting a key role of Hyp in reprogramming metabolism of cancer cells. It suggests that Hyp metabolism could be considered as a target in novel experimental strategy for cancer treatment.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"13 ","pages":"1556770"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198694","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}