Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy.

Autor:	Chen X; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. drcx1990@vip.163.com., Wang Y; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Wang JN; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Zhang YC; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Zhang YR; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Sun RX; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Qin B; Department of Ophthalmology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China., Dai YX; Department of Polymer Science and Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China., Zhu HJ; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Zhao JX; Department of Ophthalmology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China., Zhang WW; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Ji JD; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Yuan ST; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Shen QD; Department of Polymer Science and Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China., Liu QH; Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. liuqh@njmu.edu.cn.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Feb; Vol. 16 (2), pp. 294-318. Date of Electronic Publication: 2024 Jan 31.
DOI:	10.1038/s44321-024-00025-1
Abstrakt:	Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N 6 -methyladenosine (m 6 A) 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 m 6 A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO's m 6 A 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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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