tRF-Glu-CTC-005 Promotes Pathological Retinal Neovascularization via ACSL4 in Microvascular Endothelial Cells.

Pathological retinal neovascularization (RNV), a leading contributor to blindness, remains poorly understood, especially regarding the involvement of transfer RNA-derived small RNAs (tsRNAs). In this study, the mouse model of oxygen-induced retinopathy (OIR) was induced in vivo, and human retinal endothelial cells (HRECs) were applied in vitro. CCK-8, cell migration, and tube formation assays were conducted to evaluate alterations in HREC functions. tRF-Glu-CTC-005 was significantly upregulated in OIR retinas compared with controls. Overexpression of tRF-Glu-CTC-005 accelerated retinal angiogenesis and enhanced HREC functions, whereas its inhibition suppressed pathological retinal vessel growth and impaired HREC activity. Target screening identified ACSL4 as a direct downstream target of tRF-Glu-CTC-005. Inhibition of ACSL4 by PRGL493 promoted pathological RNV in the OIR mice, and reversed the anti-angiogenic effects of tRF-Glu-CTC-005 inhibition in HRECs. Mechanistically, tRF-Glu-CTC-005 negatively regulated ACSL4 expression, thereby modulating the phosphorylation of AMPKα. The biogenesis of tRF-Glu-CTC-005 under hypoxic conditions was found to involve angiogenin and stress granules. These findings unveiled that tRF-Glu-CTC-005 promotes pathological retinal angiogenesis mediated by ACSL4, offering therapeutic targets for neovascular eye diseases.