1. Academic Validation
  2. The role of vitamin K and its antagonist in the process of ferroptosis-damaged RPE-mediated CNV

The role of vitamin K and its antagonist in the process of ferroptosis-damaged RPE-mediated CNV

  • Cell Death Dis. 2025 Mar 20;16(1):190. doi: 10.1038/s41419-025-07497-0.
Xiaochan Dai # 1 Xi Yang # 1 Yifan Feng # 1 Xinyuan Wu 1 Yahan Ju 2 3 Rong Zou 1 Fei Yuan 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
  • 2 Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
  • 3 Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, PR China.
  • 4 Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China. yuanfeipaper@outlook.com.
  • # Contributed equally.
Abstract

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.

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