Molecular Therapy. Nucleic Acids最新文献_第8页

Validation of tRNA-derived fragments as diagnostic biomarkers in suspected acute stroke; limitations in analysis and quantification methods. trna衍生片段作为疑似急性脑卒中诊断生物标志物的验证分析和量化方法的局限性。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-05 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102553

Tamar Woudenberg, M Leontien van der Bent, Daphne A L van den Homberg, T Truc My Nguyen, Marieke J H Wermer, Ido R van den Wijngaard, Paul H A Quax, A Yaël Nossent, Nyika D Kruyt

{"title":"Validation of tRNA-derived fragments as diagnostic biomarkers in suspected acute stroke; limitations in analysis and quantification methods.","authors":"Tamar Woudenberg, M Leontien van der Bent, Daphne A L van den Homberg, T Truc My Nguyen, Marieke J H Wermer, Ido R van den Wijngaard, Paul H A Quax, A Yaël Nossent, Nyika D Kruyt","doi":"10.1016/j.omtn.2025.102553","DOIUrl":"10.1016/j.omtn.2025.102553","url":null,"abstract":"In acute stroke, timely diagnosis is essential to prevent extensive neuronal damage and improve patient outcomes. However, differentiating between ischemic stroke, intracerebral hemorrhage, and stroke mimics remains challenging. Transfer RNA-derived fragments (tRFs) have emerged as potential biomarkers for distinguishing between these stroke subtypes. Here we used reverse transcription-quantitative PCR (RT-qPCR) to investigate the expression of specific tRFs that we previously identified in small RNA sequencing data as potential biomarkers. Out of 12 measured tRFs, only the fragments ArgTCG53-67 and TyrGTA1-19 showed a trend for differential expression between stroke subtypes, but with insufficient predictive value to be of use in clinical practice. Combining expression data of specific tRFs into a joint model did not improve the predictive ability. Technical and computational challenges may compromise the reliability of tRF expression data from RNA sequencing, possibly explaining our inability to validate the specific tRFs as potential stroke biomarkers. Moreover, the limitations of RT-qPCR challenge a reliable quantification of these fragments even further. Our findings highlight the need for improved quantitative methods for tRF analysis to fully exploit their potential as clinically meaningful biomarkers. Addressing these technical barriers could unlock the diagnostic potential of tRFs, facilitating faster, more accurate stroke subtype identification in an acute setting.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102553"},"PeriodicalIF":6.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel PEI-aldehyde conjugates for gene delivery: Promoting chondrogenic differentiation in human mesenchymal stem cells. 用于基因传递的新型倍醛偶联物：促进人间充质干细胞的软骨分化。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-29 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102551

Diego Miranda-Balbuena, Alba Ramil-Bouzas, Naiara Doldán-Mata, Junquera López-Seijas, Juan Fafián-Labora, Ibán Lamas-Criado, Jose-Ramón Caeiro-Rey, Paco Fernández-Trillo, Ana Rey-Rico

{"title":"Novel PEI-aldehyde conjugates for gene delivery: Promoting chondrogenic differentiation in human mesenchymal stem cells.","authors":"Diego Miranda-Balbuena, Alba Ramil-Bouzas, Naiara Doldán-Mata, Junquera López-Seijas, Juan Fafián-Labora, Ibán Lamas-Criado, Jose-Ramón Caeiro-Rey, Paco Fernández-Trillo, Ana Rey-Rico","doi":"10.1016/j.omtn.2025.102551","DOIUrl":"10.1016/j.omtn.2025.102551","url":null,"abstract":"Mesenchymal stem cell (MSC) gene therapy holds significant potential for regenerative medicine, especially for treating conditions such as cartilage damage. Still, finding appropriate vectors to achieve a safe and efficient gene delivery remains a challenge. This study explores the development of novel polyethyleneimine (PEI)-based polymers functionalized with both cationic guanidinium and hydrophobic aldehyde groups for efficient transfection to human MSCs (hMSCs). PEI was chemically modified with guanidinium-(3-guanidin-N-(3-oxopropyl)propanamide [T1]) and 1-(4-formylphenyl)guanidine [T2]) and hydrophobic (octanal [T3A] and dodecanal [T3B]) aldehydes. Polyplexes were formed by the complexation of PEI-aldehyde conjugates with plasmids encoding for β-galactosidase (placZ), green fluorescent protein (pGFP), and the chondrogenic transcription factor SOX9 (psox9), and demonstrated efficient DNA complexation and protection. Among the formulations, PEI functionalized with the cationic (T2) and hydrophobic (T3A) aldehydes (PEIT2T3A) exhibited a superior transfection efficiency and biocompatibility, significantly enhancing the expression of target genes in hMSCs. Importantly, PEIT2T3A/psox9 polyplexes successfully promoted the chondrogenic differentiation of hMSCs, as evidenced by the increased expression of chondrogenic markers (SOX9, type-II collagen [COLII], and aggrecan [ACAN]) and proteoglycan deposition in aggregate cultures, while mitigating the low cell viability found with unmodified PEI. These findings suggest that PEIT2T3A is a promising non-viral vector for targeted gene delivery and hMSC-based regenerative medicine applications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102551"},"PeriodicalIF":6.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Removal of dsRNA byproducts using affinity chromatography. 亲和色谱法去除dsRNA副产物。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-29 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102549

Nathaniel E Clark, Mateusz Kozarski, Sinem Demirel Asci, Jurgen Van den Heuvel, Matt R Schraut, Roger A Winters, Kelley Kearns, Thomas C Scanlon, Senne Dillen

{"title":"Removal of dsRNA byproducts using affinity chromatography.","authors":"Nathaniel E Clark, Mateusz Kozarski, Sinem Demirel Asci, Jurgen Van den Heuvel, Matt R Schraut, Roger A Winters, Kelley Kearns, Thomas C Scanlon, Senne Dillen","doi":"10.1016/j.omtn.2025.102549","DOIUrl":"10.1016/j.omtn.2025.102549","url":null,"abstract":"Double-stranded RNA (dsRNA) molecules are immunogenic byproducts of in vitro transcription of single-stranded RNA (ssRNA). Removal of dsRNA from ssRNA is difficult because the byproducts have similar sizes, sequences, and charges to the desired ssRNA. Here, we describe a dsRNA-specific affinity resin that selectively removes dsRNA from ssRNA. Affinity purification reduced dsRNA levels by >100-fold, to as low as ∼0.00007% w/w of total mRNA, with no negative impact on RNA integrity. The purified RNA, synthesized with standard nucleotides, induced no inflammatory response in a reporter cell line assay designed to measure innate immune responses. Purified RNA induced greater protein expression and healthier cells. The immunogenicity of the affinity-purified RNA with standard nucleotides compares favorably to RNA synthesized with modified nucleotides and purified with cellulose or reverse-phase high-performance liquid chromatography (HPLC). dsRNA affinity purification provides a facile and scalable solution to the problem of immunogenic dsRNA byproducts in transcribed RNA. This approach will improve quality and safety of RNA vaccines and therapeutics.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102549"},"PeriodicalIF":6.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antisense oligonucleotide targeting nicotinamide N-methyltransferase exhibits antitumor effects. 以烟酰胺n -甲基转移酶为靶点的反义寡核苷酸具有抗肿瘤作用。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-29 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102548

Tomoaki Hara, Sikun Meng, Yuuya Kasahara, Takashi Osawa, Daisuke Motooka, Hiromichi Sato, Yasuko Arao, Yoshiko Saito, Kana Inoue, Yumiko Hamano, Yuichiro Doki, Hidetoshi Eguchi, Satoshi Obika, Hideshi Ishii

{"title":"Antisense oligonucleotide targeting nicotinamide N-methyltransferase exhibits antitumor effects.","authors":"Tomoaki Hara, Sikun Meng, Yuuya Kasahara, Takashi Osawa, Daisuke Motooka, Hiromichi Sato, Yasuko Arao, Yoshiko Saito, Kana Inoue, Yumiko Hamano, Yuichiro Doki, Hidetoshi Eguchi, Satoshi Obika, Hideshi Ishii","doi":"10.1016/j.omtn.2025.102548","DOIUrl":"10.1016/j.omtn.2025.102548","url":null,"abstract":"Nicotinamide N-methyltransferase (NNMT) is one of the methyltransferase family genes. It consumes S-adenosyl-l-methionine (SAM), which is required for DNA methylation and histone methylation for epigenetic regulation, to produce 1-methylnicotinamide from nicotinamide, a source of NAD+, thus affecting energy metabolism and epigenetics. Recent studies have shown that NNMT is highly expressed in cancer tissues, mainly in the stroma, and worsens prognosis. Therefore, NNMT is attracting attention as a new target for cancer therapy. In this study, we generated 2',4'-BNA/LNA-modified gapmer phosphorothioate antisense oligonucleotides that inhibit NNMT expression and examined their antitumor effects. The antisense oligonucleotide candidates were finally narrowed down to eight sequences, and when they were examined for their inhibitory effect on NNMT expression in cancer cells, all of the sequences showed inhibitory effects. The most effective one was conjugated with a small molecule compound that targets the stroma of cancer tissues. The antitumor effect was examined in a mouse model of cancer cell transplantation, and the antitumor effect was enhanced in the group treated with the antisense oligonucleotide. These results indicate that NNMT antisense oligonucleotide drugs targeting the stroma are promising as novel anticancer agents.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102548"},"PeriodicalIF":6.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanoparticle-formulated mRNA encoding engineered multivalent SIRPα-Fc fusion proteins shows robust anti-cancer activity in preclinical models. 在临床前模型中，纳米颗粒配制的mRNA编码工程多价SIRPα-Fc融合蛋白显示出强大的抗癌活性。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-29 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102550

Shruti Lal, Adrienne Sallets, Srinivasa R Bandi, Gowrisudha Adusumilli, Weiqun Liu, Ray Low, Kimmy Ferry, Chris MacDonough, Mahmoud ElAzzouny, Ole A W Haabeth, Colin J McKinlay, Pei-Ken Hsu, Anushtha Sharma, Pragyesh Dhungel, Jenna Triplett, Meredith Leong, Evan McCartney-Melstad, Samuel Deutsch, Kannan Gunasekaran

{"title":"Nanoparticle-formulated mRNA encoding engineered multivalent SIRPα-Fc fusion proteins shows robust anti-cancer activity in preclinical models.","authors":"Shruti Lal, Adrienne Sallets, Srinivasa R Bandi, Gowrisudha Adusumilli, Weiqun Liu, Ray Low, Kimmy Ferry, Chris MacDonough, Mahmoud ElAzzouny, Ole A W Haabeth, Colin J McKinlay, Pei-Ken Hsu, Anushtha Sharma, Pragyesh Dhungel, Jenna Triplett, Meredith Leong, Evan McCartney-Melstad, Samuel Deutsch, Kannan Gunasekaran","doi":"10.1016/j.omtn.2025.102550","DOIUrl":"10.1016/j.omtn.2025.102550","url":null,"abstract":"The in vivo expression of proteins by mRNA therapeutics is a transformative approach to medicine that involves expressing highly complex and therapeutically relevant molecules utilizing patients' own body. In this study, we engineered complex molecules targeting CD47 with multivalent SIRPα-Fc fusion proteins with a goal to enhance tumor specificity via formulated mRNA administration. Valency allows us to exploit antigen expression level differences between cancer and healthy cells. In vitro analysis showed that NK-mediated cytotoxicity of Tetravalent and Octavalent SIRPα was comparable to a 50,000-fold affinity-improved SIRPα molecule. However, unlike the affinity-improved SIRPα and known anti-CD47 antibodies, the Tetravalent and Octavalent SIRPα showed low to no binding to red blood cells, which also express CD47 albeit at a low level. In addition, we demonstrated in vivo efficacy of mRNAs encoding Tetravalent and Octavalent SIRPα-Fc fusion proteins and observed the complete eradication of established subcutaneous tumors in Raji mice xenograft. Further evaluation of the in-vivo-expressed proteins showed high purity, like that of the recombinant production. Differential scanning fluorimetry analysis revealed excellent thermal stability and resistance to aggregation. These results demonstrate that a significant enhancement in therapeutic window and efficacy could be achieved by engineering complex multivalent molecules.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102550"},"PeriodicalIF":6.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A single stereogenic center matters: Development of stereodefined anti-tau PMO-gapmers. 一个单一的立体中心的问题：立体定义的抗tau PMO-gapmers的发展。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-28 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102519

Suxiang Chen, Bal Hari Poudel, Rakesh Naduvile Veedu

引用次数: 0

Erratum: FUBP3 enhances HIV-1 transcriptional activity and regulates immune response pathways in T cells. 勘误：FUBP3增强HIV-1转录活性并调节T细胞的免疫反应途径。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-24 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102544

Quentin M R Gibaut, Chuan Li, Anqi Cheng, Ines Moranguinho, Luisa P Mori, Susana T Valente

引用次数: 0

Generative artificial intelligence, integrative bioinformatics, and single-cell analysis reveal Alzheimer's genetic and immune landscape. 生成人工智能，综合生物信息学和单细胞分析揭示阿尔茨海默氏症的遗传和免疫景观。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-24 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102546

Arpita Das, Manojit Bhattacharya, Ali Saber Abdelhameed, Sang-Soo Lee, Chiranjib Chakraborty

{"title":"Generative artificial intelligence, integrative bioinformatics, and single-cell analysis reveal Alzheimer's genetic and immune landscape.","authors":"Arpita Das, Manojit Bhattacharya, Ali Saber Abdelhameed, Sang-Soo Lee, Chiranjib Chakraborty","doi":"10.1016/j.omtn.2025.102546","DOIUrl":"10.1016/j.omtn.2025.102546","url":null,"abstract":"The research aims to understand Alzheimer's genetic and immune landscapes using the amalgamation of three technologies: artificial intelligence (GenAI), integrative bioinformatics, and single-cell analysis. First, the study aims to identify and characterize the significant genes associated with Alzheimer's disease (AD) using three GenAI models (GPT‑4o, Gemini model, and DeepSeek). After the genes were accumulated from GenAI models, 27 genes associated with AD were recoded. Furthermore, they were analyzed using integrative bioinformatics methods. Similarly, the immune landscape of AD using single-cell analysis was also explored, which reveals a high percentage of effector CD8+ T cells (33.42%) and naive T cells (45.95%). The single-cell study found that effector memory T cells have two subsets. It also found that the macrophage population has started to spread and dendritic cells have decreased in Alzheimer's patients. The single-cell gene expression study reveals the top ten highly expressed genes (NDUFV2, CAT, MRPS34, PBX3, THOC2, CCDC57, PBXIP1, SDHAF3, PPP4C, and MAP3K8). The clonal frequency indicates that CD8+ T and naive T cell populations show the highest clonal frequency in healthy and AD individuals and are further noted them in the clonotype cell proportion study. Following our GenAI and single-cell profiling strategy, future studies will help in quickly understanding the genetic and immune basis of many diseases.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102546"},"PeriodicalIF":6.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12148819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deconvolution of cargo delivery and immunogenicity following intranasal delivery of mRNA lipid nanoparticle vaccines. 鼻内递送mRNA脂质纳米颗粒疫苗后货物递送和免疫原性的反褶积。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-24 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102547

Mai N Vu, Devaki Pilapitiya, Andrew Kelly, Marios Koutsakos, Stephen J Kent, Jennifer A Juno, Hyon-Xhi Tan, Adam K Wheatley

{"title":"Deconvolution of cargo delivery and immunogenicity following intranasal delivery of mRNA lipid nanoparticle vaccines.","authors":"Mai N Vu, Devaki Pilapitiya, Andrew Kelly, Marios Koutsakos, Stephen J Kent, Jennifer A Juno, Hyon-Xhi Tan, Adam K Wheatley","doi":"10.1016/j.omtn.2025.102547","DOIUrl":"10.1016/j.omtn.2025.102547","url":null,"abstract":"Intranasal vaccination aims to elicit mucosal immunity in the respiratory tract to better protect against respiratory infections (e.g., SARS-CoV-2 and influenza). Most vaccines, including recent COVID-19 mRNA lipid nanoparticles (LNPs), are optimized for intramuscular (i.m.) administration and typically perform poorly when delivered intranasally. Here, we prepared mRNA-LNPs using clinically approved ionizable lipids (ALC-0315, SM-102, and DLin-MC3-DMA) with or without a permanent cationic lipid (1,2-dioleoyl-3-trimethylammonium-propane [DOTAP]) to deliver a model immunogen (ovalbumin [OVA]) and CRE recombinase reporter mRNA. Using wild-type C57BL/6 and Ai14 reporter mouse models, we deconvoluted the effects of LNP formulation on mRNA cargo delivery and immunogenicity following i.m. or intranasal (i.n.) administration. After i.m. vaccination, mRNA-LNPs demonstrated transfection of muscle and immune cells in vivo, and consequently robust humoral immune responses. In contrast, mRNA-LNP delivery to the respiratory mucosa was poorly immunogenic, both in naive animals and in those with post-infection inflammation. Encouragingly, mRNA-LNPs efficiently transfected epithelial and immune cells within the lungs and expressed mRNA cargo could efficiently recall immunity in draining secondary lymphoid tissues. The addition of DOTAP led to enhanced recall responses. Decoding interplays of LNP formulations and their performance in vivo within specific tissue compartments will provide principles that can guide the rational design of mRNA-LNPs for maximal protection against respiratory diseases.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102547"},"PeriodicalIF":6.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12138548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hyperandrogen-induced imbalance of FOXO4-AR regulatory loop contributes to ovulatory disorders in polycystic ovary syndrome. 高雄激素诱导的FOXO4-AR调节环失衡与多囊卵巢综合征的排卵障碍有关。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-20 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102543

Ruiqiong Zhou, Zhaoyi Wang, Mei Dong, Songlu Wang, Xiangyuan Li, Junjiu Huang, Xiqian Zhang, Fenghua Liu

{"title":"Hyperandrogen-induced imbalance of FOXO4-AR regulatory loop contributes to ovulatory disorders in polycystic ovary syndrome.","authors":"Ruiqiong Zhou, Zhaoyi Wang, Mei Dong, Songlu Wang, Xiangyuan Li, Junjiu Huang, Xiqian Zhang, Fenghua Liu","doi":"10.1016/j.omtn.2025.102543","DOIUrl":"10.1016/j.omtn.2025.102543","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility, and its underlying mechanisms remain largely unknown. Our study aimed to investigate the role of FOXO4 in PCOS and its possible regulatory mechanisms. Decreased FOXO4 and CDKN1A expressions and increased androgen receptor (AR) and CCND1 expressions were observed in granulosa cells (GCs) from patients with PCOS. Luteinizing hormone (LH) surge induced upregulation of FOXO4 and CDKN1A and downregulation of AR and CCND1 in vitro and in vivo. FOXO4 inhibited cell proliferation and cell cycle progression and partially mediated the induction of CCND1 and CDKN1A expressions by LH surge. Knockdown of FOXO4 in rat ovaries led to a PCOS-like model, and hyperandrogenism was responsible for reduced FOXO4 expression in ovaries of PCOS in vitro and in vivo. AR-mediated androgen action is known to play a key role in the development of PCOS. Notably, AR repressed FOXO4 expression by binding to its promoter, whereas FOXO4 inhibited AR protein levels through protease degradation, thus establishing a regulatory loop between AR and FOXO4 that was disrupted by hyperandrogenism. This study demonstrates that hyperandrogenism inhibits LH surge formation and disrupts the regulatory balance between FOXO4 and AR, which may contribute to the continued exacerbation of PCOS.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102543"},"PeriodicalIF":6.5,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0