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Current management focuses primarily on supportive care, highlighting an urgent need to identify novel treatment targets. Neuronal expression of the enzyme histone deacetylase 3 (HDAC3) has been previously implicated in retinal ganglion cell (RGC) degeneration after optic nerve crush (ONC), a model of TON. Here we investigated the role of myeloid HDAC3 (i.e., HDAC3 expressed in microglia and macrophages) in RGC loss, axonal degeneration, and efferocytosis, a reparative process by which phagocytic myeloid cells engulf apoptotic cells. ONC injury was performed on myeloid-specific HDAC3 knockout (KO) and floxed control mice. Neurodegeneration and efferocytosis assays were assessed using retina flatmount immunolabeling and confocal imaging. RGC function was evaluated using pattern electroretinography (PERG). Axonal sprouting was quantified by anterograde transport of cholera toxin B injected intravitreally. Myelin debris clearance was assessed in optic nerves in vivo and in vitro using bone-marrow-derived macrophages isolated from myeloid HDAC3 KO and control mice. Myeloid HDAC3 deletion preserved RGC and improved axonal regeneration after ONC, together with improved retinal function assessed by PERG. Furthermore, the deletion of HDAC3 enhanced the phagocytic function of myeloid cells to effectively remove apoptotic cells and myelin debris, both in vivo and in vitro. These protective effects were associated with the deletion of HDAC3 specifically in macrophages, since microglial-only deletion of HDAC3 did not preserve RGC count or function. The enhanced efferocytosis function of HDAC3 KO macrophages was at least partly dependent on increasing the expression of the phagocytic tyrosine kinase receptor, MerTK. The deletion of myeloid HDAC3 enhances efferocytosis, leading to neuroprotection, regeneration, and functional recovery following ONC. Targeting myeloid-HDAC3 presents a novel therapeutic strategy for TON.<\/jats:p>","DOI":"10.1038\/s41420-026-03030-0","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:51:50Z","timestamp":1773874310000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myeloid HDAC3 deletion protects against traumatic optic injury"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6403-9404","authenticated-orcid":false,"given":"Rami A.","family":"Shahror","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol A.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashlynn","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piyanan","family":"Chuesiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3042-9425","authenticated-orcid":false,"given":"Abdelrahman Y.","family":"Fouda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"3030_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.860070","volume":"13","author":"NPB Au","year":"2022","unstructured":"Au NPB, Ma CHE. 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