Lactylated histone H4K8 regulation of MFN2/Wnt signaling integrates glycolytic metabolism and Müller cell activation in the pathogenesis of glaucoma

Elevated intraocular pressure (IOP) imposes a substantial glycolytic demand on retinal tissue, driving excessive lactate production to sustain neuronal energy homeostasis. In the present study, we demonstrate that this metabolic stress markedly increases histone H4 lysine 8 lactylation (H4K8la) throughout the glaucomatous retina. Genome-wide profiling using Cleavage Under Targets and Tagmentation (CUT&Tag) revealed pronounced and selective H4K8la enrichment within the promoter region of mitofusin-2 (MFN2), a key mitochondrial fusion GTPase. Functionally, suppression of MFN2 mediated by H4K8la reciprocally enhances β-catenin expression, particularly under oxidative stress, indicating the existence of a lactate-responsive epigenetic circuit that couples mitochondrial dynamics to activation of the Wnt/β-catenin signaling pathway. In vivo experiments demonstrated that activated Müller glia orchestrate synchronous mitochondrial remodeling in retinal ganglion cells (RGCs) and photoreceptors. We propose that MFN2 functions as a molecular conduit, enabling intercellular mitochondrial transfer between Müller glia and neurons to sustain elevated glycolytic flux. This metabolic reprogramming increases lactate release, stimulates Wnt/β-catenin pathway activation, and ultimately leads to RGC apoptosis. Single-cell RNA sequencing (scRNA-seq) further revealed intensified Müller–amacrine/bipolar cell communication under ocular hypertension, accompanied by a marked reduction in neurexin- and VEGF-mediated interactions. Collectively, these findings identify a lactylation-governed epigenetic checkpoint that links mitochondrial dysfunction to glial–neuronal metabolic coupling in glaucoma, nominating MFN2 as a potential neuroprotective therapeutic target. • Elevated intraocular pressure (IOP) induces histone lactylation (H4K8la) in the retina, linking metabolic stress to epigenetic changes. • H4K8la deposition on the MFN2 promoter suppresses its expression, activating the Wnt/β-catenin pathway and promoting retinal ganglion cell apoptosis. • Müller glial cells mediate mitochondrial transfer, maintaining metabolic coupling in glaucoma models. • The lactylation-driven epigenetic circuit connects mitochondrial dysfunction to retinal neurodegeneration in glaucoma. • Inhibition of lactate metabolism or Wnt signaling protects against retinal damage, suggesting therapeutic targets for glaucoma.