Hangjia Zuo , Xianyang Liu , Bingjing Lv , Ning Gao , Miaomiao Du , Xiang Gao , Yongguo Xiang , Rongxi Huang , Meiting Lin , Yakun Wang , Yonglin Chen , Hong Cheng , Tong Zhang , Shijie Zheng , Wenjuan Wan , Ke Hu
{"title":"自噬诱导的NR2F1激活通过靶向STAT3促进晶状体上皮细胞凋亡,促进白内障相关纤维化","authors":"Hangjia Zuo , Xianyang Liu , Bingjing Lv , Ning Gao , Miaomiao Du , Xiang Gao , Yongguo Xiang , Rongxi Huang , Meiting Lin , Yakun Wang , Yonglin Chen , Hong Cheng , Tong Zhang , Shijie Zheng , Wenjuan Wan , Ke Hu","doi":"10.1016/j.gendis.2025.101549","DOIUrl":null,"url":null,"abstract":"<div><div>Cataracts, a widely prevalent ocular pathology, engender visual impairment and emerge as a primary etiological factor contributing to ocular blindness. Substantial evidence substantiates that epithelial–mesenchymal transition stands prominently among the pivotal causative factors associated with this debilitating condition. However, the underlying mechanism remains unclear. In the present study, we analyzed the single-cell data and found that the mRNA expression of nuclear receptor subfamily 2 group F member 1 (NR2F1/COUP-TFI) was notably decreased in fibrocytes compared with epithelium. Interestingly, we observed a significant up-regulation of NR2F1 protein in the anterior subcapsular cataract mice model and transforming growth factor-β1 (TGF-β1)-treated SRA01/04 cells. Furthermore, we found that TGF-β1 stimulation disrupted the balance of autophagy, leading to impaired degradation and increased protein levels of NR2F1 in SRA01/04 cells. Subsequently, after anterior chamber injection of NR2F1 adeno-associated virus in anterior subcapsular cataract mice, the development of fibrosis was alleviated. <em>In vitro</em>, the knockdown of NR2F1 in SRA01/04 also mitigated the TGF-β1-induced epithelial–mesenchymal transition. Mechanically, NR2F1 proteins directly interacted with the promoter region of STAT3 and orchestrated the up-regulation of phosphorylated STAT3 (p-STAT3), thereby facilitating the apoptosis and migration of SRA01/04 cells via the JAK1/STAT3 pathway, resulting in epithelium fibrosis and cataracts. Furthermore, inhibition of p-STAT3 obviously attenuated apoptosis and fibrosis of SRA01/04 cells. Collectively, our study provides a novel therapeutic target for cataracts and offers insight into the underlying mechanism of the epithelial–mesenchymal transition of cataracts.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101549"},"PeriodicalIF":9.4000,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Autophagy-induced NR2F1 activation promotes the apoptosis of lens epithelial cells and facilitates cataract-associated fibrosis through targeting STAT3\",\"authors\":\"Hangjia Zuo , Xianyang Liu , Bingjing Lv , Ning Gao , Miaomiao Du , Xiang Gao , Yongguo Xiang , Rongxi Huang , Meiting Lin , Yakun Wang , Yonglin Chen , Hong Cheng , Tong Zhang , Shijie Zheng , Wenjuan Wan , Ke Hu\",\"doi\":\"10.1016/j.gendis.2025.101549\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Cataracts, a widely prevalent ocular pathology, engender visual impairment and emerge as a primary etiological factor contributing to ocular blindness. Substantial evidence substantiates that epithelial–mesenchymal transition stands prominently among the pivotal causative factors associated with this debilitating condition. However, the underlying mechanism remains unclear. In the present study, we analyzed the single-cell data and found that the mRNA expression of nuclear receptor subfamily 2 group F member 1 (NR2F1/COUP-TFI) was notably decreased in fibrocytes compared with epithelium. Interestingly, we observed a significant up-regulation of NR2F1 protein in the anterior subcapsular cataract mice model and transforming growth factor-β1 (TGF-β1)-treated SRA01/04 cells. Furthermore, we found that TGF-β1 stimulation disrupted the balance of autophagy, leading to impaired degradation and increased protein levels of NR2F1 in SRA01/04 cells. Subsequently, after anterior chamber injection of NR2F1 adeno-associated virus in anterior subcapsular cataract mice, the development of fibrosis was alleviated. <em>In vitro</em>, the knockdown of NR2F1 in SRA01/04 also mitigated the TGF-β1-induced epithelial–mesenchymal transition. Mechanically, NR2F1 proteins directly interacted with the promoter region of STAT3 and orchestrated the up-regulation of phosphorylated STAT3 (p-STAT3), thereby facilitating the apoptosis and migration of SRA01/04 cells via the JAK1/STAT3 pathway, resulting in epithelium fibrosis and cataracts. Furthermore, inhibition of p-STAT3 obviously attenuated apoptosis and fibrosis of SRA01/04 cells. Collectively, our study provides a novel therapeutic target for cataracts and offers insight into the underlying mechanism of the epithelial–mesenchymal transition of cataracts.</div></div>\",\"PeriodicalId\":12689,\"journal\":{\"name\":\"Genes & Diseases\",\"volume\":\"12 5\",\"pages\":\"Article 101549\"},\"PeriodicalIF\":9.4000,\"publicationDate\":\"2025-01-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genes & Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2352304225000388\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genes & Diseases","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2352304225000388","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Autophagy-induced NR2F1 activation promotes the apoptosis of lens epithelial cells and facilitates cataract-associated fibrosis through targeting STAT3
Cataracts, a widely prevalent ocular pathology, engender visual impairment and emerge as a primary etiological factor contributing to ocular blindness. Substantial evidence substantiates that epithelial–mesenchymal transition stands prominently among the pivotal causative factors associated with this debilitating condition. However, the underlying mechanism remains unclear. In the present study, we analyzed the single-cell data and found that the mRNA expression of nuclear receptor subfamily 2 group F member 1 (NR2F1/COUP-TFI) was notably decreased in fibrocytes compared with epithelium. Interestingly, we observed a significant up-regulation of NR2F1 protein in the anterior subcapsular cataract mice model and transforming growth factor-β1 (TGF-β1)-treated SRA01/04 cells. Furthermore, we found that TGF-β1 stimulation disrupted the balance of autophagy, leading to impaired degradation and increased protein levels of NR2F1 in SRA01/04 cells. Subsequently, after anterior chamber injection of NR2F1 adeno-associated virus in anterior subcapsular cataract mice, the development of fibrosis was alleviated. In vitro, the knockdown of NR2F1 in SRA01/04 also mitigated the TGF-β1-induced epithelial–mesenchymal transition. Mechanically, NR2F1 proteins directly interacted with the promoter region of STAT3 and orchestrated the up-regulation of phosphorylated STAT3 (p-STAT3), thereby facilitating the apoptosis and migration of SRA01/04 cells via the JAK1/STAT3 pathway, resulting in epithelium fibrosis and cataracts. Furthermore, inhibition of p-STAT3 obviously attenuated apoptosis and fibrosis of SRA01/04 cells. Collectively, our study provides a novel therapeutic target for cataracts and offers insight into the underlying mechanism of the epithelial–mesenchymal transition of cataracts.
期刊介绍:
Genes & Diseases is an international journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
Aims and Scopes
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.