Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China.
Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China.
Cell Rep. 2023 Jul 25;42(7):112779. doi: 10.1016/j.celrep.2023.112779. Epub 2023 Jul 11.
Retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV) are predominant features of age-related macular degeneration (AMD), with an unclear mechanism. Herein, we show that RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) is up-regulated in AMD. In RPE cells, ALKBH5 overexpression associates with depolarization, oxidative stress, disturbed autophagy, irregular lipid homeostasis, and elevated VEGF-A secretion, which subsequently promotes proliferation, migration, and tube formation of vascular endothelial cells. Consistently, ALKBH5 overexpression in mice RPE correlates with various pathological phenotypes, including visual impairments, RPE anomalies, choroidal neovascularization (CNV), and interrupted retinal homeostasis. Mechanistically, ALKBH5 regulates retinal features through its demethylation activity. It targets PIK3C2B and regulates the AKT/mTOR signaling pathway with YTHDF2 as the N-methyladenosine reader. IOX1, an ALKBH5 inhibitor, suppresses hypoxia-induced RPE dysfunction and CNV progression. Collectively, we demonstrate that ALKBH5 induces RPE dysfunction and CNV progression in AMD via PIK3C2B-mediated activation of the AKT/mTOR pathway. Pharmacological inhibitors of ALKBH5, like IOX1, are promising therapeutic options for AMD.
视网膜色素上皮 (RPE) 功能障碍和脉络膜新生血管 (CNV) 是年龄相关性黄斑变性 (AMD) 的主要特征，其机制尚不清楚。在此，我们表明 RNA 去甲基酶 α-酮戊二酸依赖性双加氧酶 alkB 同源物 5 (ALKBH5) 在 AMD 中上调。在 RPE 细胞中，ALKBH5 的过表达与去极化、氧化应激、自噬紊乱、脂质稳态异常和 VEGF-A 分泌增加有关，这随后促进了血管内皮细胞的增殖、迁移和管腔形成。一致地，在小鼠 RPE 中过表达 ALKBH5 与各种病理表型相关，包括视力障碍、RPE 异常、脉络膜新生血管 (CNV) 和视网膜内稳态中断。在机制上，ALKBH5 通过其去甲基化活性调节视网膜特征。它靶向 PIK3C2B 并通过 YTHDF2 作为 N-甲基腺苷读取器调节 AKT/mTOR 信号通路。IOX1 是一种 ALKBH5 抑制剂，可抑制缺氧诱导的 RPE 功能障碍和 CNV 进展。总的来说，我们证明 ALKBH5 通过 PIK3C2B 介导的 AKT/mTOR 通路的激活诱导 AMD 中的 RPE 功能障碍和 CNV 进展。ALKBH5 的药理学抑制剂，如 IOX1，是 AMD 的有前途的治疗选择。
