Single-cell RNA sequencing reveals lipid metabolism disorders in the retina in spontaneous high myopia.

Abstract

Background: Myopia is one of the most common eye diseases affecting children and adolescents, with its etiology often attributed to a combination of genetic and environmental factors. This study utilized single-cell RNA sequencing (scRNA-seq) technology to investigate gene expression differences between guinea pigs with spontaneous high myopia (SHM) and those with normal vision.

Results: Lens-induced myopia (LIM) and SHM guinea pigs exhibit significant retinal structural abnormalities and functional impairments, characterized by reduced retinal thickness and abnormal electroretinogram (ERG) responses, indicating progressive retinal dysfunction during myopia development. scRNA-seq and molecular experiments revealed that the ceramide synthase 5 (CERS5) / ceramide synthase 6 (CERS6) / alkaline ceramidase 3 (ACER3) / phospholipid phosphatase 1 (PLPP1) / prosaposin (PSAP) / UDP-glucose ceramide glucosyltransferase (UGCG) signaling axis is significantly activated in the retinas of myopic guinea pigs, suggesting dysregulation of sphingolipid metabolism. These changes were associated with an increased expression of SPHK1 and a shift in receptor expression from S1PR1 to S1PR2, indicating a transition in lipid signaling from a physiological state to a stress-related pathological state. Additionally, the activation of the P62/NRF2/KEAP1 pathway confirmed enhanced oxidative stress in the myopic retina. This study demonstrates that the CERS5/CERS6/ACER3/PLPP1/PSAP/UGCG signaling axis mediates disruption of sphingolipid metabolism and oxidative stress in the myopic guinea pig retina.

Conclusions: The present study demonstrates that the CERS5/CERS6/ACER3/PLPP1/PSAP/UGCG signaling axis mediates sphingolipid metabolic dysregulation and oxidative stress in the retinas of myopic guinea pigs. Mechanistically, the abnormal activation of the SPHK1-S1P signaling pathway, the shift in receptors from S1PR1 to S1PR2, and the subsequent activation of the P62/KEAP1/NRF2 pathway collectively led to changes in retinal morphology (such as reduced thickness) and functional impairment. These findings establish a mechanistic link between lipid metabolic imbalance and retinal pathology in myopia offering potential therapeutic targets for preventing retinal damage associated with myopia.