2. Academic Validation
  3. Enhanced ferroptosis sensitivity promotes the formation of highly myopic cataract via the DDR2-Hippo pathway

Enhanced ferroptosis sensitivity promotes the formation of highly myopic cataract via the DDR2-Hippo pathway

  • Cell Death Dis. 2025 Feb 3;16(1):64. doi: 10.1038/s41419-025-07384-8.
Dongling Guo # 1 2 3 4,  Yu Du # 1 2 3 4,  Xin Liu 1 2 3 4,  Dan Li 1 2 3 4,  Ling Wei 1 2 3 4,  Xiangjia Zhu 5 6 7 8
Affiliations

Affiliations

  • 1 Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
  • 2 Key Laboratory of Myopia and Related Eye Diseases, NHC; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 3 Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
  • 4 State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
  • 5 Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China. zhuxiangjia1982@126.com.
  • 6 Key Laboratory of Myopia and Related Eye Diseases, NHC; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China. zhuxiangjia1982@126.com.
  • 7 Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China. zhuxiangjia1982@126.com.
  • 8 State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. zhuxiangjia1982@126.com.
  • # Contributed equally.
PMID: 39900894 DOI: 10.1038/s41419-025-07384-8
Abstract

Highly myopic cataract (HMC) is a leading cause of blindness among the working-age individuals, with its pathogenesis poorly understood. This study aimed to elucidate the role of Ferroptosis in HMC development as well as the underlying mechanisms. In HMC lens epithelia, levels of Fe2+ and lipid peroxidation were found elevated, with increased vulnerability towards Ferroptosis as revealed by transmission electron microscopy. Mechanistically, RNA Sequencing of HMC lens epithelial samples identified up-regulated expression of Discoidin Domain Receptor tyrosine kinase 2 (DDR2) as a key factor, which could enhance Ferroptosis sensitivity via the Src-Hippo pathway. Specifically, DDR2 interacted with Src kinase, leading to the nuclear translocation of homologous transcriptional regulators (yes-associated protein 1 [YAP1] and WW domain containing transcription regulator 1 [WWTR1]) of the Hippo pathway, which altered the expression level of ferroptosis-related genes. Notably, highly myopic eyes of mice exhibited higher sensitivity to RSL3, a Ferroptosis inducer, manifested as more severe nuclear lens opacities both in vitro and in vivo compared with the contralateral control eyes, which could be alleviated by inhibitors of either Ferroptosis or DDR2. Altogether, these findings highlighted the role of DDR2 in mediating Ferroptosis in HMC formation, providing a novel insight for therapeutic interventions.

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