# Ethambutol induces optic neuropathy through SDHB-mediated ferroptosis in retinal ganglion cells via Smad4 pathway

## TL;DR

This study shows that ethambutol causes optic neuropathy by triggering ferroptosis in retinal cells through the SDHB and Smad4 pathway.

## Contribution

The study identifies SDHB and Smad4 as key factors in ethambutol-induced optic neuropathy via ferroptosis.

## Key findings

- Ethambutol treatment causes retinal ganglion cell death primarily through ferroptosis.
- Ethambutol inhibits SDHB expression and disrupts antioxidant defenses.
- Smad4 interacts with SDHB's promoter region, and this interaction is inhibited by ethambutol.

## Abstract

Ethambutol (EMB)-induced optic neuropathy (EON) is a clinical concern. Ferroptosis, involving iron and toxic reactive oxygen species (ROS), causes unique cell death, but its mechanism in EON is unclear. This study aims to explore the EON mechanisms. Wistar rats were used to establish an EON model by administering EMB at 50 mg/kg daily for 8 weeks. Retinal ganglion cells (RGC-5 cells) were used for in vitro experiments. Histological staining, MTT assays, flow cytometry, western blot analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, and high-throughput sequencing were conducted to investigate cell death modes and molecular changes. EMB treatment leads to significant cell loss and structural damage in RGCs of EON model, predominantly through ferroptosis. We confirm increased ROS levels, downregulation of SLC7A11 and GPX4, and decreased glutathione (GSH) levels, upregulation of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels in EMB-treated RGC-5 cells. Furthermore, sequencing data reveal that in RGC-5 cells treated with EMB, the differentially expressed genes (DEGs) primarily exhibited alterations in biological functions associated with metabolism, stress response, and apoptotic regulation. Specifically, EMB inhibits the expression of succinate dehydrogenase enzyme B (SDHB), thereby disrupting antioxidant defenses and facilitating ferroptosis. Moreover, Smad4 has been pinpointed as a pivotal transcription factor in regulating SDHB expression. Notably, its interaction with the promoter region of SDHB is inhibited by EMB. This study provides compelling evidence for the involvement of ferroptosis in EON and highlights SDHB and Smad4 as potential therapeutic targets for mitigating this adverse effect.

The online version contains supplementary material available at 10.1007/s13577-025-01342-4.