Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world, and timely prevention and treatment are very important. Previously, we found that a neurodegenerative factor, Glia maturation factor-beta (GMFB), was upregulated in the vitreous at a very early stage of diabetes, which may play an important role in pathogenesis. Here, we found that in a high glucose environment, large amounts of GMFB protein can be secreted in the vitreous, which translocates the ATPase ATP6V1A from the lysosome, preventing its assembly and alka-linizing the lysosome in the retinal pigment epithelial (RPE) cells. ACSL4 protein can be recognized by HSC70, the receptor for chaperone-mediated autophagy, and finally digested in the lysosome. Abnormalities in the autophagy-lysosome degradation process lead to its accumulation, which catalyzes the production of lethal lipid species and finally induces ferroptosis in RPE cells. GMFB antibody, lysosome activator NKH477, CMA activator QX77, and ferroptosis inhibitor Liproxstatin-1 were all effective in preventing early diabetic retinopathy and maintaining normal visual function, which has powerful clinical application value. Our research broadens the understanding of the relationship between autophagy and ferroptosis and provides a new therapeutic target for the treatment of DR.

Automated summary

Diabetic retinopathy (DR) is a major cause of blindness, and timely prevention and treatment are crucial. This study found that the neurodegenerative factor GMFB is upregulated in the early stages of diabetes and plays a role in the pathogenesis of the disease. In a high glucose environment, GMFB secretion in the vitreous affects lysosome function, autophagy, and ferroptosis, leading to abnormalities in the degradation process and the accumulation of lethal lipid species in the retinal pigment epithelial cells. Targeting GMFB and related pathways could be a new therapeutic strategy for DR.