Ranitidine protects Müller cells against ferroptosis in diabetic retinopathy by regulating the AKT1/GSK3β pathway

  • Indian J Ophthalmol. 2026 Feb 1;74(2):250-258. doi: 10.4103/IJO.IJO_1522_25.
Wei He  1  2  3 ,  Jialong Qi  4 ,  Zhongjian Liu  5 ,  Yan Mei  1  2  3
Affiliations
  • 1. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, P.R. China.
  • 2. Department of Ophthalmology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, P.R. China.
  • 3. Medical School, Kunming University of Science and Technology, Kunming, Yunnan, P.R. China.
  • 4. Department of Gastroenterology, Yunnan Digestive Endoscopy Clinical Medical Center, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, P.R. China.
  • 5. Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, P.R. China.
PMID: 41581041 DOI: 10.4103/IJO.IJO_1522_25
Abstract

Purpose: This study was designed to investigate the primary targets and possible mechanisms of ranitidine (Ra) against diabetic retinopathy (DR).

Methods: Single-cell Sequencing technology and the SPIED3 platform were employed to characterize key genes in retinal Müller cells (RMCs) of diabetic mice and identify potential small-molecule compounds separately. The effects of small-molecule compounds on the cell viability and proliferative capacity of mouse retinal Müller cells (rMC-1) cultured in high-glucose (HG) were evaluated using the cell counting kit-8 (cck-8) and 5-ethyl-2-deoxyuridine (Edu) assay. Glutathione (GSH), malondialdehyde (MDA), Reactive Oxygen Species (ROS), and Fe2+ were identified as indicators of Ferroptosis. Then, network pharmacology was used to predict specific targets for Ra. Western blotting was used to identify ferroptosis-related proteins, including Glutathione Peroxidase 4 (GPX4), cystine/glutamate transporter (xCT), serine/threonine-protein kinase Akt1, and glycogen synthase kinase-3β (GSK3β).

Results: The predicted results suggested that the potential mechanism of RMCs damage in diabetic mice is associated with Ferroptosis. The cck-8 results indicated Ra played a regulatory role in HG-induced rMC-1 by enhancing cell viability. Besides, Edu results showed that Ra promoted the proliferation of rMC-1 cells. Network pharmacological analyses predicted a potential mechanism of Ra effect in HG-induced rMC-1, mainly associated with the Akt1 and GSK3β genes. Phenotypically, Ra elevated intracellular GSH levels, while reducing MDA, Fe²⁺, and ROS concentrations. Mechanistically, Ra increased xCT and GPX4 expression through the promotion of Akt1/GSK3β phosphorylation, thereby alleviating Ferroptosis in HG-induced rMC-1 cells.

Conclusions: The study highlighted that the mechanism of DR is closely associated with Ferroptosis and demonstrated that Ra inhibits HG-induced Ferroptosis of rMC-1 cells by regulating the Akt1/GSK3β signaling pathway, thereby providing a theoretical basis for using Ra in managing DR.

Keywords
diabetic retinopathy; ferroptosis; ranitidine.
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