Protective role of Oxyresveratrol against NaIO3-induced oxidative stress in RPE cells via targeting NRF2-mediated ferroptosis in vitro and in vivo

  • Eur J Pharmacol. 2026 Jan 10:1010:178402. doi: 10.1016/j.ejphar.2025.178402.
Chih-Chun Chuang  1 ,  Yong-Syuan Chen  2 ,  Wei-Yang Lu  3 ,  Shih-Chi Su  4 ,  Ting-Yu Liao  5 ,  Shun-Fa Yang  6 ,  Yi-Hsien Hsieh  7
Affiliations
  • 1. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Ophthalmology, Changhua Christian Hospital, Changhua, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
  • 2. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
  • 3. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Ophthalmology, Changhua Christian Hospital, Changhua, Taiwan; Department of Optometry, Chung Shan Medical University, Taichung, Taiwan.
  • 4. Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 5. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
  • 6. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: [email protected].
  • 7. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: [email protected].
PMID: 41308856 DOI: 10.1016/j.ejphar.2025.178402
Abstract

Age-related macular degeneration (AMD) is a chronic retinal disorder that occurs when oxidative damages are gradually accumulated to the center of retina. Oxyresveratrol (OxyR), a naturally occurring stilbene found in many Plants, has been reported to exhibit anti-inflammatory and anti-oxidative activities. To fill this gap, we explored the effect of OxyR on retinal pigment epithelial cells in response to oxidative stress and on a mouse model of AMD and further dissected the molecular mechanism underlying OxyR's actions. In this study, we demonstrated that OxyR efficiently impeded both Apoptosis and Ferroptosis of a human ARPE-19 cells induced by sodium iodate (NaIO3). Such protective effect of OxyR on NaIO3-induced ARPE-19 cells was accompanied with altered expression levels of NRF2, KEAP1, and several ferroptosis-related proteins. Moreover, OxyR treatment, coupled with silencing of NRF2, Ferroptosis inhibitor (ferrostatin-1) or depletion of ROS, enhanced the protection of ARPE-19 cells from NaIO3-induced damages. Consistently, oral gavage of OxyR restored the reduction of retinal thickness and attenuated the upregulation of NRF2 in retinal pigment epithelium layers of NaIO3-treated mice. These results demonstrated that OxyR mitigates NaIO3-induced ARPE19 cell death via targeting NRF2-ferroptosis signaling. Our findings provided potential avenues for the use of OxyR in controlling AMD.

Keywords
Age-related macular degeneration; Ferroptosis; Oxidative stress; Oxyresveratrol; Retinal pigment epithelium; Sodium iodate.
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