Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy
Abstract Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-01-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00025-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849311101649420288 |
|---|---|
| author | Xue Chen Ying Wang Jia-Nan Wang Yi-Chen Zhang Ye-Ran Zhang Ru-Xu Sun Bing Qin Yuan-Xin Dai Hong-Jing Zhu Jin-Xiang Zhao Wei-Wei Zhang Jiang-Dong Ji Song-Tao Yuan Qun-Dong Shen Qing-Huai Liu |
| author_facet | Xue Chen Ying Wang Jia-Nan Wang Yi-Chen Zhang Ye-Ran Zhang Ru-Xu Sun Bing Qin Yuan-Xin Dai Hong-Jing Zhu Jin-Xiang Zhao Wei-Wei Zhang Jiang-Dong Ji Song-Tao Yuan Qun-Dong Shen Qing-Huai Liu |
| author_sort | Xue Chen |
| collection | DOAJ |
| description | Abstract Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC–microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO’s m6A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients. |
| format | Article |
| id | doaj-art-6a40c1bfa3554e66b172849242c8d92f |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-6a40c1bfa3554e66b172849242c8d92f2025-08-20T03:53:32ZengSpringer NatureEMBO Molecular Medicine1757-46842024-01-0116229431810.1038/s44321-024-00025-1Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathyXue Chen0Ying Wang1Jia-Nan Wang2Yi-Chen Zhang3Ye-Ran Zhang4Ru-Xu Sun5Bing Qin6Yuan-Xin Dai7Hong-Jing Zhu8Jin-Xiang Zhao9Wei-Wei Zhang10Jiang-Dong Ji11Song-Tao Yuan12Qun-Dong Shen13Qing-Huai Liu14Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The Affiliated Suqian First People’s Hospital of Nanjing Medical UniversityDepartment of Polymer Science and Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE, School of Chemistry and Chemical Engineering, Nanjing UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The Affiliated Suqian First People’s Hospital of Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Polymer Science and Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE, School of Chemistry and Chemical Engineering, Nanjing UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical UniversityAbstract Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC–microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO’s m6A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients.https://doi.org/10.1038/s44321-024-00025-1Diabetic Retinopathy (DR)FTON6-Methyladenosine (m6A)Vascular Endothelial CellsPericyte |
| spellingShingle | Xue Chen Ying Wang Jia-Nan Wang Yi-Chen Zhang Ye-Ran Zhang Ru-Xu Sun Bing Qin Yuan-Xin Dai Hong-Jing Zhu Jin-Xiang Zhao Wei-Wei Zhang Jiang-Dong Ji Song-Tao Yuan Qun-Dong Shen Qing-Huai Liu Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy EMBO Molecular Medicine Diabetic Retinopathy (DR) FTO N6-Methyladenosine (m6A) Vascular Endothelial Cells Pericyte |
| title | Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy |
| title_full | Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy |
| title_fullStr | Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy |
| title_full_unstemmed | Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy |
| title_short | Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy |
| title_sort | lactylation driven fto targets cdk2 to aggravate microvascular anomalies in diabetic retinopathy |
| topic | Diabetic Retinopathy (DR) FTO N6-Methyladenosine (m6A) Vascular Endothelial Cells Pericyte |
| url | https://doi.org/10.1038/s44321-024-00025-1 |
| work_keys_str_mv | AT xuechen lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT yingwang lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT jiananwang lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT yichenzhang lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT yeranzhang lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT ruxusun lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT bingqin lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT yuanxindai lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT hongjingzhu lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT jinxiangzhao lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT weiweizhang lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT jiangdongji lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT songtaoyuan lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT qundongshen lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy AT qinghuailiu lactylationdrivenftotargetscdk2toaggravatemicrovascularanomaliesindiabeticretinopathy |