Reprogramming Glial Cell Metabolism via a tRNA Fragment Preserves Vision in Retinal Neurodegeneration

Retinal neurodegeneration leads to progressive and irreversible vision loss driven by retinal ganglion cell (RGC) death, yet effective neuroprotective therapies remain lacking. Recent studies suggest that small non-coding RNAs play key roles in central nervous system injury, but their relevance to retinal neurodegeneration remains incompletely understood. Here, we identify a significant increase in 5'tiRNA-His-GTG, an ANG-generated tRNA-derived fragment, in mouse models of retinal neurodegeneration. Functionally, elevated 5'tiRNA-His-GTG promotes reactive gliosis and contributes to RGC degeneration through Müller cell-RGC crosstalk. Conversely, inhibition of 5'tiRNA-His-GTG attenuates glial activation, preserves RGC survival, and improves visual function and vision-dependent behaviors. Mechanistically, 5'tiRNA-His-GTG induces neurodegenerative changes by suppressing the LPCAT1-mediated phosphatidylcholine (PC) biosynthetic pathway and perturbing glycerophospholipid metabolism. Notably, restoration of LPCAT1 expression or PC levels reverses 5'tiRNA-His-GTG-induced neurodegeneration both in vitro and in vivo. These findings uncover a previously unrecognized 5'tiRNA-His-GTG-LPCAT1-PC regulatory pathway that contributes to retinal neurodegeneration. Collectively, our study identifies 5'tiRNA-His-GTG as a critical mediator of glial-driven neuroinflammation and neuronal loss, and highlights this signaling axis as a potential therapeutic target for retinal neurodegeneration.