MG53 Coordinates Macrophage Polarization and Neuroimmune Coupling to Promote Corneal Nerve Regeneration via the MPEG1-MVP-STAT6 Axis.

Corneal sensory nerve plays a critical role in pain sensation and corneal wound healing. However, the molecular mechanisms that regulate corneal nerve repair, especially couple immune regulation to corneal nerve repair remain poorly understood. Here, Mitsugumin 53 (MG53), a E3 ubiquitin ligase, is identified as a pivotal regulator of macrophage-mediated corneal nerve regeneration. MG53 is present in tear film, aqueous humor, and corneal epithelial cells, suggesting its role in corneal homeostasis. In an alkali burn injury model, genetic ablation of MG53 impairs nerve regrowth, whereas genetic overexpression or delivery of MG53 modified RNA markedly enhanced corneal nerve regeneration. Mechanistically, MG53 interacts with major vault protein (MVP) and promotes its K63-linked ubiquitination at lysine 747, facilitating STAT6 nuclear translocation and transcriptionally activating M2 (reparative) macrophage genes. MG53 overexpression biases macrophage polarization toward a reparative phenotype characterized by elevated Arg1, Fizz1, Ym1/2, and IRF4 expression, thereby enhancing clearance of degenerating nerve fragments and promoting nerve regeneration. Using a genome-wide Membrane Proteome Array (MPA) screen, macrophage-expressed gene 1 (MPEG1) is identified as a putative receptor mediating MG53 internalization in macrophages. These findings establish a mechanistic framework in which circulating MG53 engages the MPEG1-MVP-STAT6 axis to coordinate macrophage polarization and neuroimmune repair.