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

## TL;DR

This study shows that DUSP4 protects retinal pigment epithelium from aging and degeneration, offering a new therapeutic target for AMD.

## Contribution

The study identifies DUSP4 as a novel regulator of RPE senescence and AMD progression.

## Key findings

- DUSP4 knockdown in mice worsened AMD symptoms compared to controls.
- DUSP4 overexpression reversed senescence markers in knockout cells.
- DUSP4 inhibits p53, p38, and NF-kB pathways to regulate RPE health.

## 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.