ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway.

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 N⁶-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. [Display omitted] • ALKBH5 is up-regulated in clinical AMD specimens, hypoxic RPE cells, and CNV mice • ALKBH5 triggers oxidative stress, disturbed autophagy, and irregular lipid homeostasis in RPE • ALKBH5 overexpression in mice RPE disturbed retinal homeostasis and promoted CNV progression • ALKBH5 modulates PIK3C2B mRNA stability as an m⁶A eraser with YTHDF2 as the reader Sun et al. demonstrate that the N⁶-methyladenosine demethylase ALKBH5 induces RPE dysfunction and CNV progression in AMD via PIK3C2B-mediated activation of the AKT/mTOR pathway. They also reveal IOX1, an ALKBH5 inhibitor, as a pharmacological option for AMD. They offer insights into the molecular mechanism and therapeutic strategies for AMD. [ABSTRACT FROM AUTHOR]