As a novel ferroptosis inhibitor, primaquine alleviates I/R-induced retinal neuron death via increasing GSTA1 activity
Year: 2026
Type: article
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. • Primaquine can inhibit ferroptosis induced by I/R injury in vivo and in vitro . • Primaquine can inhibit ferroptosis induced by Erastin or RSL3 in R28 cells. • GSTA1 acts as a key factor in primaquine’s inhibition of ferroptosis. • GSTA1 deficiency reverses Primaquine’s inhibition of the ferroptosis induced by OGD/R, Erastin or RSL3 in R28 cells.
Source: Biomedicine & Pharmacotherapy
Authors: Shuang Lu, Lewen Wang, Keting Wang, Kun Xiong, Weitao Yan
Institutions: Central South University, Hainan Medical University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,610
OpenAlex ID: W7123363009