Age-related macular degeneration (AMD) is a complex disease caused by different genetic and environmental risk factors leading to loss of cells in the central part of the retina. Oxidative stress appears to be an important environmental risk factor that contributes to both the initiation and progression of AMD. Retinal pigment epithelium (RPE) plays an important role in regulating oxidative stress in the retina and is one of the main retinal cell types affected in AMD. A main function of RPE is to phagocytose photoreceptor outer segments (POS) which are rich in the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA), making this cell type potentially more susceptible to oxidative stress-induced lipid peroxidation which can lead to cell death. RPE is known to undergo necrotic cell death in response to oxidative stress. The aim of this study was to determine if DHA in POS can increase oxidative damage to RPE. It was found that RPE undergo increased lipid peroxidation and decreased cell viability when stressed with hydrogen peroxide in combination with DHA or POS. H₂O₂-induced oxidative stress was found to cause both ferroptosis and necroptosis. However, the ferroptosis regulator acyl-CoA synthetase long-chain family member 4 (ACSL4) was found to be downregulated in RPE exposed to H₂O₂ and this effect was exacerbated when the RPE cells were simultaneously treated with DHA. Together, these results show a response of RPE when stressed which will likely be overwhelmed under disease conditions such as AMD resulting in cell death.

年龄相关性黄斑变性（AMD）是一种复杂的疾病，由不同的遗传和环境危险因素引起，导致视网膜中央部分细胞损失。氧化应激似乎是一个重要的环境风险因素，有助于 AMD 的发生和进展。视网膜色素上皮 (RPE) 在调节视网膜氧化应激中发挥着重要作用，是 AMD 受影响的主要视网膜细胞类型之一。 RPE 的主要功能是吞噬富含多不饱和脂肪酸 (PUFA) 二十二碳六烯酸 (DHA) 的光感受器外节 (POS)，使这种细胞类型可能更容易受到氧化应激诱导的脂质过氧化的影响，从而导致细胞死亡。众所周知，RPE 会因氧化应激而发生坏死性细胞死亡。本研究的目的是确定 POS 中的 DHA 是否会增加 RPE 的氧化损伤。研究发现，当过氧化氢与 DHA 或 POS 结合使用时，RPE 会经历脂质过氧化增加和细胞活力降低。发现H ₂ O ₂诱导的氧化应激可引起铁死亡和坏死性凋亡。然而，铁死亡调节剂酰基辅酶A合成酶长链家族成员4 (ACSL4)被发现在暴露于H ₂ O ₂的RPE中下调，并且当RPE细胞同时用DHA处理时，这种效应加剧。总之，这些结果显示了 RPE 在受到压力时的反应，在 AMD 等疾病条件下可能会被压垮，导致细胞死亡。