{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T16:42:34Z","timestamp":1786207354424,"version":"build-2736575974"},"reference-count":28,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271114"],"award-info":[{"award-number":["82271114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["LZ22H120001"],"award-info":[{"award-number":["LZ22H120001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["KYYW202227"],"award-info":[{"award-number":["KYYW202227"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["82271114"],"award-info":[{"award-number":["82271114"]}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["LZ22H120001"],"award-info":[{"award-number":["LZ22H120001"]}]},{"name":"Natural Science Foundation of Zhejiang Province","award":["KYYW202227"],"award-info":[{"award-number":["KYYW202227"]}]},{"name":"Wenzhou Medical University","award":["82271114"],"award-info":[{"award-number":["82271114"]}]},{"name":"Wenzhou Medical University","award":["LZ22H120001"],"award-info":[{"award-number":["LZ22H120001"]}]},{"name":"Wenzhou Medical University","award":["KYYW202227"],"award-info":[{"award-number":["KYYW202227"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The retinal pigment epithelium (RPE) serves as a critical guardian of subretinal homeostasis, with its dysfunction implicated in major retinal pathologies, including age-related macular degeneration (AMD) and retinitis pigmentosa. While cellular senescence has emerged as a key driver of RPE degeneration, the molecular mechanisms underlying this process remain incompletely defined. Emerging evidence implicates dual-specificity phosphatase 4 (DUSP4) in cellular stress responses through its antioxidant and anti-inflammatory capacities, yet its role in RPE pathophysiology remains unexplored. Our study reveals a compensatory increase in DUSP4 expression during AMD-associated RPE senescence. To functionally characterize this observation, we knocked down DUSP4 in the RPE of mice via subretinal injection of AAV-shDUSP4. In a sodium iodate-induced dry AMD model, mice with DUSP4 knockdown presented more severe visual impairment than control mice did. To further investigate the molecular mechanism, stable DUSP4-knockout cell lines were constructed via CRISPR\/Cas9 technology. The high expression of senescence markers in the DUSP4-knockout cell lines was reversed by DUSP4 overexpression. Furthermore, DUSP4 coordinates the modulation of cell cycle, stress response, and pro-inflammatory signaling by inhibiting the p53, p38, and NF-kB pathways. These findings establish DUSP4 as a multi-functional regulator of RPE senescence. Our work not only elucidates a novel DUSP4-dependent mechanism in AMD pathogenesis but also highlights its therapeutic potential for preserving RPE function in AMD.<\/jats:p>","DOI":"10.3390\/ijms26083735","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T10:49:54Z","timestamp":1744714194000},"page":"3735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration"],"prefix":"10.3390","volume":"26","author":[{"given":"Xiyuan","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoze","family":"Ni","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxin","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqin","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongduan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zai-Long","family":"Chi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S0140-6736(22)02609-5","article-title":"Age-related macular degeneration","volume":"401","author":"Guymer","year":"2023","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ophtha.2019.09.024","article-title":"Age-Related Macular Degeneration Preferred Practice Pattern(R)","volume":"127","author":"Flaxel","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.ophtha.2011.09.027","article-title":"Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: A meta-analysis","volume":"119","author":"Rudnicka","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/j.ophtha.2020.04.019","article-title":"Prevalence and pattern of geographic atrophy in asia: The asian eye epidemiology consortium","volume":"127","author":"Rim","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1038\/s42255-021-00483-8","article-title":"The metabolic roots of senescence: Mechanisms and opportunities for intervention","volume":"3","author":"Wiley","year":"2021","journal-title":"Nat. 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