Ketogenic diet attenuates Müller cell activation and retinal neuroinflammation in autoimmune glaucoma through acetylation-mediated FOXO signalling

Abstract

Glaucoma consists of a group of neurodegenerative diseases characterized by retinal ganglion cell degeneration, in which Müller cells are increasingly recognised as drivers of neuroinflammation. A ketogenic diet (KD) elevates circulating β-hydroxybutyrate (BHB) and exhibits benefits in other neurodegenerative disorders; however, its role in glaucoma remains poorly understood. In the present study, an experimental autoimmune glaucoma (EAG) mouse model was established and primary Müller cells were cultured. Using spectrophotometry, optical coherence tomography and immunofluorescence, serum ketone body levels were found to be significantly lower in both patients with primary open-angle glaucoma and EAG mice, independent of intraocular pressure. In vitro and in vivo experiments showed that KD increased BHB levels and ketone body metabolism, suppressed Müller cell activation and reduced retinal neuroinflammation. In addition, 4D data-independent acquisition proteomic analysis and subsequent validation revealed that FOXO3A acetylation and FOXO3A and metallothionein 2A upregulation were regulated in the retina and Müller cells. These findings suggest that impaired ketone body metabolism occurs in glaucoma and that KD-mediated neuroprotection is associated with altered FOXO3A acetylation. The present study highlighted an association between ketone metabolism and immune regulation in glaucoma, providing evidence for Müller cell phenotypic modulation and supported further investigation of KD as a potential neuroprotective adjunct therapy for glaucoma.