The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.

中文翻译：

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谷胱甘肽过氧化物酶 4 （GPX4） 缺乏导致晶状体发育异常和新生儿白内障


人体晶状体由单层晶状体上皮细胞 （LEC） 和细长的纤维组成，这些纤维紧密排列但被质膜隔开。晶状体质膜的完整性对于维持晶状体细胞结构、体内平衡和透明度至关重要。谷胱甘肽过氧化物酶 4 （GPX4） 是一种硒酶，在防止脂质过氧化方面起着关键作用。本研究旨在阐明 GPX4 在使用体外、离体和体内系统进行晶状体发育过程中晶状体质膜稳定性中的作用。我们的研究结果表明，GPX4 缺陷触发晶状体上皮细胞凋亡非依赖性但铁死亡介导的细胞死亡。离体培养过程中阻断晶状体 GPX4 活性会诱导晶状体混浊、LEC 死亡和晶状体纤维细胞排列的破坏。晶状体特异性 Gpx4 的缺失导致不饱和磷脂的显著损失和氧化磷脂的增加。因此，Gpx4 缺陷的晶状体表现出晶状体纤维细胞结构的大量破坏，通过铁死亡导致 LEC 的显着丢失，以及新生儿白内障的形成。值得注意的是，在胚胎第 9.5 天给孕妇施用脂质过氧化抑制剂 liproxstatin-1 可显着防止脂质过氧化、LEC 死亡和晶状体发育缺陷。我们的研究揭示了 GPX4 在晶状体发育和透明度中的关键作用，并提供了一种成功的干预方法，通过脂质过氧化抑制来预防晶状体发育缺陷。