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Growth Arrest-specific 1 Inhibits Keap1/Nrf2 Signaling Transduction in the Activation of the Ferroptosis Program in

Rongfeng Dai1, Yu Qian1, Siqi Liu1

  • 1Department of Endocrinology, the Third People's Hospital of Changzhou, 213001 Changzhou, Jiangsu, China.

Frontiers in Bioscience (Landmark Edition)
|March 28, 2025
PubMed
Abstract

Insights

Growth arrest-specific 1 (GAS1) promotes ferroptosis in diabetic retinopathy (DR) by inhibiting Keap1/Nrf2 signaling. Reducing GAS1 protects retinal Müller cells from high glucose-induced damage, offering a potential therapeutic target for DR.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Ophthalmology

Background:

  • Diabetic retinopathy (DR) is a microvascular complication of diabetes.
  • Growth arrest-specific 1 (GAS1) is implicated in high glucose-induced retinal Müller cell death via ferroptosis.
  • The precise role of GAS1 in DR pathogenesis remains unclear.

Purpose of the Study:

  • To investigate the role and mechanism of GAS1 in DR.
  • To explore GAS1-mediated ferroptosis in retinal Müller cells under high glucose conditions.

Main Methods:

  • Transcriptome sequencing and bioinformatic analyses (KEGG, GO) identified GAS1.
  • Assays included CCK-8, flow cytometry, and commercial kits to measure cell viability, apoptosis, lipid peroxidation, Fe2+, and oxidative stress.
  • Gene expression analysis utilized qRT-PCR and Western blotting for GAS1, Nrf2, and Keap1.

Main Results:

  • High glucose (HG) reduced Müller cell viability and glutathione (GSH) while increasing apoptosis, lipid ROS, MDA, and Fe2+.
  • HG upregulated GAS1, Keap1, and total Nrf2, but downregulated nuclear Nrf2.
  • GAS1 knockdown improved viability and GSH, reduced apoptosis and oxidative stress markers, and increased nuclear Nrf2, while GAS1 overexpression had opposite effects. Nrf2 silencing reversed GAS1 overexpression effects.

Conclusions:

  • GAS1 inhibits Keap1/Nrf2 signaling, promoting ferroptosis in retinal Müller cells.
  • Targeting GAS1 may offer a novel therapeutic strategy for diabetic retinopathy.
Keywords:
GAS1Keap1/Nrf2Müller cellsdiabetes retinopathyferroptosis

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