Extracellular GMFB activates the non-canonical FAS-FAF1 pathway to induce lysosomal dysfunction in early diabetic retinopathy.

Diabetic retinopathy (DR) is one of the leading causes of blindness in the global working population and involves a pathological microenvironment. In early diabetes, the level of glia maturation factor-β (GMFB) is significantly elevated in the vitreous, which leads to neurodegeneration by inhibiting autophagy in the retinal pigment epithelial (RPE) cells. However, the membrane receptor of extracellular GMFB is unknown. To address this issue, this study used siRNA library screening to identify FAS as the receptor for GMFB. Furthermore, immunofluorescence and molecular docking techniques demonstrated the interaction between FAS and extracellular GMFB. FAS siRNA and its antagonist partially reversed GMFB-induced lysosomal damage in RPE cells, thereby reducing autophagosome counts. Intravitreal administration of a FAS antagonist blocked retinal dysfunction and toxic lipid peroxide accumulation in the setting of elevated GMFB or early diabetes. Mechanistically, extracellular GMFB promoted the degradation of the H-ATPase ATP6V1A by activating the ubiquitin ligand protein FAF1 via the FAS receptor. These results broaden our understanding of the FAS-FAF1-ATP6V1A axis and identify a new therapeutic target for treating early-stage DR and other retinal diseases.