# Liproxstatin-1 Attenuates Retinal Ischemia–Reperfusion Injury by Suppressing EGR1-Mediated Ferroptosis

## TL;DR

Liproxstatin-1 reduces retinal damage from ischemia-reperfusion by blocking ferroptosis through a specific molecular pathway.

## Contribution

The study identifies a novel EGR1-p53-xCT signaling axis in retinal ferroptosis and shows Liproxstatin-1 as a potential therapeutic agent.

## Key findings

- Liproxstatin-1 preserves retinal structure and partially restores visual function in ischemia-reperfusion injury.
- Liproxstatin-1 inhibits ferroptosis by downregulating EGR1, which reduces p53 and restores xCT expression.
- EGR1 knockdown using lentivirus confirms its role in ferroptosis during retinal injury.

## Abstract

Retinal ischemia–reperfusion (I/R) injury results in irreversible vision loss largely through retinal ganglion cell (RGC) death, with ferroptosis being a key mechanism. This study evaluated the therapeutic potential of the ferroptosis inhibitor Liproxstatin-1 (Lip-1) and deciphered its underlying mechanism. Using a mouse retinal I/R model and primary RGC cultures subjected to oxygen–glucose deprivation/reoxygenation (OGD/R), we demonstrated that Lip-1 effectively inhibits ferroptosis. Lip-1 treatment preserved retinal architecture (as assessed by H&E staining and SD-OCT) and partially restored visual function (as measured by electroretinography). Integrated molecular analyses—including immunofluorescence, Western blotting, and RNA sequencing—showed that Lip-1 downregulates early growth response 1 (EGR1), thereby inhibiting p53 and consequently restoring solute carrier family 7 member 11 (xCT) expression. Crucially, lentivirus-mediated EGR1 knockdown attenuated OGD/R-induced ferroptosis, confirming its pivotal role. Our work defines a coherent EGR1–p53–xCT signaling axis driving ferroptosis in retinal I/R injury and identifies Lip-1 as a neuroprotective agent targeting this pathway. These findings establish a druggable ferroptotic cascade and provide a mechanistic rationale for targeting EGR1 in the treatment of ischemic retinopathies.