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It also contributes to retinal diseases, such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Although absent in melanoma 2 (AIM2) has been linked to inflammatory disorders, autoimmune diseases, and cancers, its role in the EMT of the retinal pigment epithelium (RPE-EMT) and retinal diseases remains unclear. The present study demonstrated that AIM2 functions as a potent suppressor of RPE cell proliferation and EMT to maintain retinal homeostasis. Transcriptome analysis using RNA-sequencing (RNA-Seq) revealed that AIM2 was significantly downregulated in primary human RPE (phRPE) cells undergoing EMT and proliferation. Consequently, <jats:italic>Aim2<\/jats:italic>-deficient mice showed morphological changes and increased FN expression in RPE cells under physiological conditions, whereas AIM2 overexpression in phRPE cells inhibited EMT. In a retinal detachment-induced PVR mouse model, AIM2 deficiency promotes RPE-EMT, resulting in severe experimental PVR. Clinical samples further confirmed the downregulation of <jats:italic>AIM2<\/jats:italic> in the PVR membranes from patients. Kyoto Encyclopedia of Genes and Genome analysis revealed that the PI3K-AKT signaling pathway was significantly related to RPE-EMT and that AIM2 inhibited AKT activation in RPE cells by reducing its phosphorylation. Moreover, treatment with eye drops containing an AKT inhibitor alleviated RPE-EMT and the severity of experimental PVR. These findings provide new insights into the complex mechanisms underlying RPE-EMT and PVR pathogenesis, with implications for rational strategies for potential therapeutic applications in PVR by targeting RPE-EMT.<\/jats:p>","DOI":"10.1038\/s41419-025-07367-9","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T17:07:19Z","timestamp":1737997639000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Absent in melanoma 2: a potent suppressor of retinal pigment epithelial-mesenchymal transition and experimental proliferative vitreoretinopathy"],"prefix":"10.1038","volume":"16","author":[{"given":"Yu","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanshan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuimeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiwen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanxiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3564-1647","authenticated-orcid":false,"given":"Xiaoyin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0705-8099","authenticated-orcid":false,"given":"Ling","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"7367_CR1","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/nrm3758","volume":"15","author":"S Lamouille","year":"2014","unstructured":"Lamouille S, Xu J, Derynck R. 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