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The retinal pigment epithelium (RPE) plays a vital role in maintaining retinal homeostasis. In this study, the expression of senescence marker protein p16 is observed to be upregulated in the RPE of early DR mouse models. Transcriptomic profiling reveals that PDZ domain protein 1 (PDZK1) expression is downregulated in RPE cells after 48 hours of high\u2010glucose stimulation. Overexpression of PDZK1 reduces senescence markers in RPE cells, promoting cell proliferation and transport functions. Mechanistically, PDZK1 alleviates RPE cell senescence by interacting with 14\u20103\u20103\u03b5 to regulate the mTOR pathway, which is closely related to reducing oxidative stress and enhancing autophagy flux. In streptozotocin\u2010induced DR mouse models, both PDZK1 overexpression\u2010mediated senescence inhibition and Nutlin\u20103a\u2010induced clearance of senescent RPE cells successfully downregulate retinal senescence markers and improve early\u2010stage DR lesions. In summary, this study\u00a0identifies a novel PDZK1\u201014\u20103\u20103\u03b5\u2010mTOR axis governing high\u2010glucose\u2010induced RPE cell senescence, and provides the first direct evidence linking RPE cell senescence to DR pathogenesis. These findings reveal a promising therapeutic strategy for DR intervention.<\/jats:p>","DOI":"10.1002\/advs.202511288","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T14:36:11Z","timestamp":1756132571000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["PDZK1 Protects Against RPE Senescence by Targeting the 14\u20103\u20103\u03b5\u2010mTOR Axis to Attenuate Early Diabetic Retinopathy"],"prefix":"10.1002","volume":"12","author":[{"given":"Jian","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology The Third Affiliated Hospital Southern Medical University Guangzhou 510630 China"},{"name":"The Third School of Clinical Medicine Southern Medical University Guangzhou 510630 China"},{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases Guangzhou 510630 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The Third Affiliated Hospital Southern Medical University Guangzhou 510630 China"},{"name":"The Third School of Clinical Medicine Southern Medical University Guangzhou 510630 China"},{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases Guangzhou 510630 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The Third Affiliated Hospital Southern Medical University Guangzhou 510630 China"},{"name":"The Third School of Clinical Medicine Southern Medical University Guangzhou 510630 China"},{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases Guangzhou 510630 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The Third Affiliated Hospital Southern Medical University Guangzhou 510630 China"},{"name":"The Third School of Clinical Medicine Southern Medical University Guangzhou 510630 China"},{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases Guangzhou 510630 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The Third Affiliated Hospital Southern Medical University Guangzhou 510630 China"},{"name":"The Third School of Clinical Medicine Southern Medical University Guangzhou 510630 China"},{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases Guangzhou 510630 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chi","sequence":"additional","affiliation":[{"name":"Shenzhen Eye Hospital Shenzhen Eye Center Southern Medical University Shenzhen 518040 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8988-4276","authenticated-orcid":false,"given":"Meixia","family":"An","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology The Third Affiliated Hospital Southern Medical University Guangzhou 510630 China"},{"name":"The Third School of Clinical Medicine Southern Medical University Guangzhou 510630 China"},{"name":"Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases Guangzhou 510630 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2021.04.027"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/190724"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100919"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0420.2001.790502.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.16444"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2879-8"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.896907"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf9440"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.01.011"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2025.110314"},{"key":"e_1_2_8_11_1","first-page":"117","volume":"78","author":"Kocher O.","year":"1998","journal-title":"Lab Investig. 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