YY2 mediates transcriptional repression of PHGDH and expedites oxidative stress in retinal pigment epithelial cells in diabetic retinopathy.

AIMS/INTRODUCTION: Phosphoglycerate dehydrogenase (PHGDH), which controls serine synthesis, has been linked to retinal disease. However, there are no clues about its involvement in the diabetic retinopathy (DR) progression. Therefore, we aimed to investigate the relationship between PHGDH, serine synthesis, and DR and their underlying molecular mechanisms. METHOD: Differentially expressed genes in DR were screened using bioinformatics tools. DR mice were induced, and retinal histopathology was observed in mice. Overexpression of PHGDH was induced in the DR mice to measure l-serine, ROS, and MDA content in the retinas of DR mice. ARPE-19 cells were transfected with overexpression of PHGDH and exposed to high glucose to induce a DR in vitro model, and cell viability and apoptosis assays, serine content, and oxidative stress factor measurement were conducted. The transcriptional regulation of PHGDH by YY2 was explored by ChIP and dual-luciferase reporter assays. Finally, the combined role of YY2 and PHGDH in regulating serine synthesis, oxidative stress, and ferroptosis was investigated. RESULTS: PHGDH expression was reduced in DR mice, and overexpression of PHGDH alleviated DR progression by promoting serine synthesis and attenuating oxidative stress. YY2 bound to the promoter of PHGDH and mediated its transcriptional repression. YY2-mediated transcriptional repression of PHGDH caused disturbances in serine synthesis, leading to oxidative stress-triggered ferroptosis. CONCLUSIONS: Our data prove that YY2 plays a vital role in modulating PHGDH expression, impairing serine synthesis, and expediting oxidative stress and ferroptosis.