2. Academic Validation
  3. As a novel ferroptosis inhibitor, primaquine alleviates I/R-induced retinal neuron death via increasing GSTA1 activity

As a novel ferroptosis inhibitor, primaquine alleviates I/R-induced retinal neuron death via increasing GSTA1 activity

  • Biomed Pharmacother. 2026 Feb:195:118973. doi: 10.1016/j.biopha.2026.118973.
Shuang Lu 1,  Lewen Wang 2,  Keting Wang 3,  Kun Xiong 4,  Weitao Yan 5
Affiliations

Affiliations

  • 1 Department of Anatomy and Neurobiology, School of Xiangya Basic Medical Science, Central South University, Changsha, Hunan 410013, China. Electronic address: [email protected].
  • 2 Department of Anatomy and Neurobiology, School of Xiangya Basic Medical Science, Central South University, Changsha, Hunan 410013, China. Electronic address: [email protected].
  • 3 Department of Anatomy and Neurobiology, School of Xiangya Basic Medical Science, Central South University, Changsha, Hunan 410013, China. Electronic address: [email protected].
  • 4 Department of Anatomy and Neurobiology, School of Xiangya Basic Medical Science, Central South University, Changsha, Hunan 410013, China. Electronic address: [email protected].
  • 5 Department of Anatomy and Neurobiology, School of Xiangya Basic Medical Science, Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Brain Science Research & Transformation In Tropical Environment Of Hainan Province, Hainan Medical University, Haikou, Hainan 571199, China. Electronic address: [email protected].
PMID: 41529513 DOI: 10.1016/j.biopha.2026.118973
Abstract

Ischemia-reperfusion (I/R)-induced retinal ganglion cells (RGCs) death involves multiple types of regulated cell death. Ferroptosis plays an active role in retinal I/R injury. Primaquine, a classical antimalarial drug, has unique pharmacological properties that suggest it may inhibit Ferroptosis. We employed an acute high intraocular pressure (aHIOP) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) injury in R28 cells to investigate the effects of primaquine on retinal I/R injury. Transcriptomic Sequencing at both the animal and cellular levels identified Glutathione S-transferase alpha 1 (GSTA1) as a potential key target of primaquine. In vitro, primaquine treatment inhibited cell death induced by OGD/R, Erastin, and RSL3. It suppressed the accumulation of ROS and Fe²⁺, ameliorated mitochondrial morphological damage, and promoted the increased expression of SLC7A11 and GPX4. Primaquine administration reduced RGC layer cell loss, increased retinal thickness, and upregulated SLC7A11 and GPX4 protein levels in the retina. Knocking down GSTA1 expression reversed the protective effects of primaquine against Ferroptosis induced by OGD/R, Erastin, or RSL3. Our study offers new insights into the critical function of primaquine in inhibiting Ferroptosis via modulating GSTA1 activity in retinal neuron induced by OGD/R, Erastin, or RSL3, a mechanism that has not been previously explored.

Keywords

Ferroptosis; GSTA1; I/R; Neuron; Primaquine; Retina.

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