{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:55:43Z","timestamp":1790618143519,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Cell Communication and Signaling"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Diabetic retinopathy (DR) is the main cause of vision loss, with retinal pigment epithelial (RPE) cell dysfunction as a key contributor. Ferroptosis is implicated in RPE injury under hyperglycemia; however, its upstream regulatory mechanisms remain unclear. High glucose (HG)\u2010induced human RPE ARPE\u201019 cells and a diabetic mouse model were used. Ferroptosis was assessed through biochemical assays, Western blot, fluorescence probes, and histological staining. Protein interactions and transcriptional regulation were examined using Co\u2010IP, glutathione S\u2010transferase pull\u2010down, ChIP, and luciferase reporter assays. Immunofluorescence staining was used as key indicator expression in retinal tissues. Nuclear receptor 4A1 (NR4A1) expression was upregulated under HG\u2010induced ARPE\u201019 cells. NR4A1 knockdown alleviated HG\u2010induced iron accumulation, lipid peroxidation, and ferroptosis marker changes. Mechanistically, SMAD\u2010specific E3 ubiquitin protein ligase 2 (SMURF2) interacted with NR4A1 and promoted its ubiquitination and degradation. Forkhead box O6 (FOXO6) was upregulated by HG and repressed SMURF2 transcription. SMURF2 overexpression mitigated HG\u2010induced ARPE\u201019 ferroptosis and retinal injury in DR mice, an effect reversed by NR4A1 co\u2010overexpression. SMURF2 knockdown reversed the effect of FOXO6 knockdown on HG\u2010induced ferroptosis in ARPE\u201019 cells and retinal injury in DR mice. The FOXO6\u2013SMURF2\u2013NR4A1 axis critically regulates ferroptosis in RPE cells during DR.<\/jats:p>","DOI":"10.1002\/ccs3.70108","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:16:10Z","timestamp":1787728570000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXO6 inhibits SMURF2\u2010mediated ubiquitination and degradation of NR4A1 to promote retinal pigment epithelial cell ferroptosis in diabetic retinopathy"],"prefix":"10.1002","volume":"20","author":[{"given":"Qiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Renmin Hospital of Wuhan University  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pathology Medical School of Yangtze University  Jingzhou Hubei 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