Age-related macular degeneration (AMD) is the leading cause of irreversible vision damage among elderly individuals. There is still no efficient treatment for dry AMD. Retinal pigment epithelial (RPE) degeneration has been confirmed to play an important role in dry AMD. Recent studies have reported that ferroptosis caused by iron overload and lipid peroxidation may be the primary causes of RPE degeneration. However, the upstream regulatory molecules of RPE ferroptosis remain largely unknown. Pigment epithelium-derived factor (PEDF) is an important endogenic protective factor for the RPE. Our results showed that in the murine dry AMD model induced by sodium iodate (SI), PEDF expression was downregulated. Moreover, dry AMD-like pathology was observed in PEDF-knockout mice. Therefore, the aim of this study was to reveal the effects and mechanism of PEDF on RPE ferroptosis and investigate potential therapeutic targets for dry AMD. The results of lipid peroxidation and transmission electron microscope showed that retinal ferroptosis was significantly activated in SI-treated mice and PEDF-knockout mice. Restoration of PEDF expression ameliorated SI-induced retinal dysfunction in mice, as assessed by electroretinography and optical coherence tomography. Mechanistically, western blotting and immunofluorescence analysis demonstrated that the overexpression of PEDF could upregulate the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain-1 (FTH1), which proved to inhibit lipid peroxidation and RPE ferroptosis induced by SI. This study revealed the novel role of PEDF in ferroptosis inhibition and indicated that PEDF might be a potential therapeutic target for dry AMD.

年龄相关性黄斑变性（AMD）是老年人不可逆视力损伤的主要原因。对于干性 AMD 仍然没有有效的治疗方法。视网膜色素上皮（RPE）变性已被证实在干性 AMD 中发挥重要作用。最近的研究表明，铁过载和脂质过氧化引起的铁死亡可能是RPE变性的主要原因。然而，RPE 铁死亡的上游调控分子仍然很大程度上未知。色素上皮衍生因子（PEDF）是 RPE 的重要内源性保护因子。我们的结果表明，在碘酸钠（SI）诱导的小鼠干性 AMD 模型中，PEDF 表达下调。此外，在 PEDF 敲除小鼠中观察到干性 AMD 样病理。因此，本研究的目的是揭示PEDF对RPE铁死亡的影响和机制，并探讨干性AMD的潜在治疗靶点。脂质过氧化和透射电镜结果显示，SI处理的小鼠和PEDF敲除小鼠的视网膜铁死亡显着激活。通过视网膜电图和光学相干断层扫描评估，恢复 PEDF 表达可改善 SI 诱导的小鼠视网膜功能障碍。从机制上来说，蛋白质印迹和免疫荧光分析表明，PEDF的过表达可以上调谷胱甘肽过氧化物酶4（GPX4）和铁蛋白重链1（FTH1）的表达，从而抑制SI诱导的脂质过氧化和RPE铁死亡。这项研究揭示了 PEDF 在抑制铁死亡中的新作用，并表明 PEDF 可能是干性 AMD 的潜在治疗靶点。