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Article

The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration

by
Xiyuan Liu
,
Zhaoze Ni
,
Jing Zhang
,
Xiaoyan Lin
,
Chenxin Wu
,
Yuyang Wu
,
Lingqin Dong
,
Zongduan Zhang
* and
Zai-Long Chi
*
State Key Laboratory of Eye Health, Eye Hospital of Wenzhou Medical University, Wenzhou 325035, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(8), 3735; https://doi.org/10.3390/ijms26083735
Submission received: 14 March 2025 / Revised: 11 April 2025 / Accepted: 12 April 2025 / Published: 15 April 2025
(This article belongs to the Section Molecular Pharmacology)
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Abstract

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.
Keywords: dual-specificity phosphatase 4; retinal pigment epithelium; senescence; age-related macular degeneration dual-specificity phosphatase 4; retinal pigment epithelium; senescence; age-related macular degeneration

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MDPI and ACS Style

Liu, X.; Ni, Z.; Zhang, J.; Lin, X.; Wu, C.; Wu, Y.; Dong, L.; Zhang, Z.; Chi, Z.-L. The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration. Int. J. Mol. Sci. 2025, 26, 3735. https://doi.org/10.3390/ijms26083735

AMA Style

Liu X, Ni Z, Zhang J, Lin X, Wu C, Wu Y, Dong L, Zhang Z, Chi Z-L. The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration. International Journal of Molecular Sciences. 2025; 26(8):3735. https://doi.org/10.3390/ijms26083735

Chicago/Turabian Style

Liu, Xiyuan, Zhaoze Ni, Jing Zhang, Xiaoyan Lin, Chenxin Wu, Yuyang Wu, Lingqin Dong, Zongduan Zhang, and Zai-Long Chi. 2025. "The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration" International Journal of Molecular Sciences 26, no. 8: 3735. https://doi.org/10.3390/ijms26083735

APA Style

Liu, X., Ni, Z., Zhang, J., Lin, X., Wu, C., Wu, Y., Dong, L., Zhang, Z., & Chi, Z.-L. (2025). The Protective Role of DUSP4 in Retinal Pigment Epithelium Senescence and Degeneration. International Journal of Molecular Sciences, 26(8), 3735. https://doi.org/10.3390/ijms26083735

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