FGF21 protects retinal pigment epithelium from sodium iodate-induced injury: Association with inhibition of ferroptosis and the NRF2/GPX4 pathway.

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness, with retinal pigment epithelium (RPE) cell death representing a central pathological event. Ferroptosis, an iron-dependent form of regulated cell death, has recently been implicated in RPE degeneration. Although fibroblast growth factor 21 (FGF21) has demonstrated cytoprotective effects in various contexts, its specific role and mechanism in RPE protection, particularly concerning ferroptosis, remain unexplored. This study investigated the protective effect of FGF21 against sodium iodate (NaIO3)-induced damage and its underlying mechanism, with a focus on ferroptosis. In vitro, NaIO3 treatment induced significant injury in ARPE-19 cells, which was effectively rescued by FGF21 co-treatment. The protective efficacy of FGF21 was comparable to that of the specific ferroptosis inhibitor Ferrostatin-1. Mechanistically, FGF21 alleviated intracellular iron overload in ARPE-19 cells by modulating the expression of iron regulators (CD71 and FPN1), reduced lipid peroxidation, and restored glutathione levels. Mechanistic exploration revealed that FGF21 treatment was associated with the upregulation of NRF2 and HO-1 and, crucially, with the attenuation of GPX4 downregulation. In a NaIO3-induced mouse model of retinal degeneration, FGF21 administration significantly preserved retinal structure, as evidenced by the maintained outer nuclear layer and total retinal thickness in optical coherence tomography (OCT) and histological analyses. Consistent with the cellular findings, FGF21 upregulated GPX4, NRF2, and HO-1 protein expression in retinal tissues. Our findings demonstrate that FGF21 protects ARPE-19 cells and the retina from NaIO3-induced damage. Its protective profile is closely associated with the mitigation of key ferroptosis hallmarks and correlates with the modulation of the NRF2/GPX4 antioxidant axis. This study provides novel insights and important preclinical evidence supporting further investigation into FGF21 as a potential therapeutic agent for ferroptosis-related retinal degenerative diseases.