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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\u2010mediated 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\u2010linked 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\u2010wide Membrane Proteome Array (MPA) screen, macrophage\u2010expressed 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\u2013MVP\u2013STAT6 axis to coordinate macrophage polarization and neuroimmune repair.<\/jats:p>","DOI":"10.1002\/advs.202523002","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T15:25:59Z","timestamp":1775834759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MG53 Coordinates Macrophage Polarization and Neuroimmune Coupling to Promote Corneal Nerve Regeneration via the MPEG1\u2013MVP\u2013STAT6 Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Peng","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhentao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"},{"name":"College of Optometry The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Sollenberger","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahide","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerthika","family":"Sathish","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usman","family":"Alizai","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Pawlik","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Chandler","sequence":"additional","affiliation":[{"name":"College of Optometry The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7136-7326","authenticated-orcid":false,"given":"Hua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Surgery The Ohio State University Wexner Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"13","article-title":"Corneal Innervation and Sensation: The Eye and Beyond","volume":"91","author":"Yang A. 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