Dai Xiaochan, Yang Xi, Feng Yifan, Wu Xinyuan, Ju Yahan, Zou Rong, Yuan Fei
Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
Cell Death Dis. 2025 Mar 20;16(1):190. doi: 10.1038/s41419-025-07497-0.
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in people over the age of 55. AMD currently affects approximately 8% of the world's population, and the number is growing as the global population ages. Growing evidence suggests that pathological choroidal neovascularization (CNV) is often related to more severe and rapid vision loss and blindness associated with AMD. The typical clinical treatment is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents. However, some patients do not respond well to this therapy, and the potential risks of long-term repeated injections cannot be ignored. Therefore, there is an urgent need to explore the specific mechanisms of CNV development and find new, safe, and effective treatments. In this study, our data indicate that ferroptotic damage of retinal pigment epithelium (RPE) and its induced VEGFA overexpression are critical promoting factors in the development of CNV. Vitamin K can mediate the protection of RPE cells from ferroptotic damage and regulate the expression of eIF2α-ATF4-VEGFA in a VKOR/FSP1-dependent manner, inhibiting new angiogenesis to alleviate CNV. On the contrary, vitamin K antagonists (VKA) represented by warfarin, can promote RPE ferroptotic damage and related vascular proliferation in mice and eventually aggravate CNV lesions. However, vitamin K still showed significant protective effects even in the presence of VKA. Due to its significant anti-ferroptosis and anti-neovascular effects, as well as its relative safety and convenience of use, vitamin K has excellent potential in the treatment of CNV and is expected to become a clinically effective and safe new CNV treatment strategy.
年龄相关性黄斑变性（AMD）是55岁以上人群不可逆视力丧失的主要原因。目前，AMD影响着全球约8%的人口，且随着全球人口老龄化，这一数字还在不断增加。越来越多的证据表明，病理性脉络膜新生血管形成（CNV）通常与AMD相关的更严重、更快速的视力丧失和失明有关。典型的临床治疗方法是玻璃体内注射抗血管内皮生长因子（抗VEGF）药物。然而，一些患者对这种治疗反应不佳，长期反复注射的潜在风险也不容忽视。因此，迫切需要探索CNV发生发展的具体机制，并寻找新的、安全有效的治疗方法。在本研究中，我们的数据表明，视网膜色素上皮（RPE）的铁死亡损伤及其诱导的VEGFA过表达是CNV发生发展的关键促进因素。维生素K可以介导对RPE细胞铁死亡损伤的保护，并以VKOR/FSP1依赖的方式调节eIF2α-ATF4-VEGFA的表达，抑制新生血管生成以减轻CNV。相反，以华法林为代表的维生素K拮抗剂（VKA）可促进小鼠RPE铁死亡损伤及相关血管增殖，最终加重CNV病变。然而，即使在存在VKA的情况下，维生素K仍显示出显著的保护作用。由于其显著的抗铁死亡和抗新生血管作用，以及相对安全和使用方便，维生素K在CNV治疗中具有优异的潜力，有望成为一种临床有效且安全的新型CNV治疗策略。
