2. Academic Validation
  3. Pipecolic acid mitigates ferroptosis in diabetic retinopathy by regulating GPX4-YAP signaling

Pipecolic acid mitigates ferroptosis in diabetic retinopathy by regulating GPX4-YAP signaling

  • Biomed Pharmacother. 2023 Nov 18:169:115895. doi: 10.1016/j.biopha.2023.115895.
Liying Luo 1,  Yuying Cai 2,  Yanyun Jiang 1,  Yingying Gong 1,  Chunyang Cai 3,  Dongwei Lai 3,  Xiao Jin 4,  Zhiqiang Guan 5,  Qinghua Qiu 6
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
  • 2 Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, PR China.
  • 3 Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, PR China.
  • 4 Department of Rheumatology and Immunology, Xuzhou Municipal Hospital Affiliated with Xuzhou Medical University, Xuzhou, Jiangsu PR China.
  • 5 Department of Dermatology, Xuzhou Municipal Hospital Affiliated with Xuzhou Medical University, Xuzhou, Jiangsu, PR China. Electronic address: [email protected].
  • 6 Department of Ophthalmology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address: [email protected].
PMID: 37984309 DOI: 10.1016/j.biopha.2023.115895
Abstract

Diabetic retinopathy (DR) is currently recognized as the leading cause of end-stage eye disease. Pipecolic acid, a metabolite, has a significant regulatory effect on several pathological processes. However, the exact mechanism by which it causes damage in diabetic retinopathy is unknown. Between September 2021 and December 2022, 40 patients were retrospectively examined and divided into two groups: the healthy group (n = 20) and the DR group (n = 20). Metabolomic analysis found that pipecolic acid plays an important role in this process. Streptozotocin-induced diabetic mice and high-glucose cultured human retinal capillary endothelial cells (HRCECs) were then treated with pipecolic acid. Several oxidative stress measurements and RNA sequencing of retinal cells were tested. A gene interaction study was conducted using bioinformatics. Comparison of serological metabolites between healthy volunteers and DR patients showed that pipecolic acid was significantly lower in DR patients, and there was a negative correlation between the level of pipecolic acid with blood glucose and glycated hemoglobin. Yes-associated protein (YAP) mRNA, Malondialdehyde (MDA), and Reactive Oxygen Species (ROS) levels were significantly higher in diabetic mice, but Glutathione Peroxidase (GSH-Px) levels were significantly lower. Pipecolic acid significantly alleviated oxidative stress and YAP expression. The number of vascular tubes was significantly higher in the DR group, and pipecolic acid treatment significantly reduced tube formation. RNA-Sequencing analysis revealed that YAP and glutathione-dependent lipid hydroperoxidase Glutathione Peroxidase 4 (GPX4) expression was reduced, and functional enrichment analysis revealed that Ferroptosis and Hippo signaling pathways play an important role in this process. Additionally, pipecolic acid's ability to improve DR is diminished after YAP and GPX4 ablation. This study found that pipecolic acid, as a metabolite, may impede the progression of DR by inhibiting the YAP-GPX4 signaling pathway.

Keywords

Diabetic retinopathy; Ferroptosis; GPX4; Pipecolic acid; YAP.

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