# Dihydroartemisinin Alleviates Neuronal Damage and Seizures in Epileptic Mice by Inhibiting Ferroptosis via the SIRT1/FOXO1/SLC7A11/GPX4 Pathway

## TL;DR

Dihydroartemisinin reduces seizures and brain damage in epileptic mice by blocking a type of cell death called ferroptosis through a specific molecular pathway.

## Contribution

The study reveals a novel mechanism by which dihydroartemisinin inhibits ferroptosis via the SIRT1/FOXO1/SLC7A11/GPX4 pathway in epilepsy.

## Key findings

- DHA reduced seizures and hippocampal neuronal damage in epileptic mice.
- DHA inhibited ferroptosis by increasing SLC7A11 and GPX4 expression.
- DHA activated SIRT1, which reduced FOXO1 acetylation and enhanced SLC7A11 transcriptional activity.

## Abstract

Epilepsy represents a prevalent neurological disorder. Currently, ferroptosis has been reported to be intricately linked to epilepsy onset and progression. Dihydroartemisinin (DHA) can inhibit the level of ferroptosis in various diseases. Therefore, the present study investigated whether DHA could inhibit seizures and display neuroprotective impacts by impeding ferroptosis.

In the KA‐induced epileptic mouse model, the effects of DHA on epileptic behavior, cognitive function, and hippocampal neuronal damage were observed. Using both in vivo and in vitro models, the impact of DHA on neuronal injury and ferroptosis‐related markers was investigated. Techniques including molecular docking, Western Blot, immunofluorescence, and CHIP‐qPCR were utilized to analyze the regulatory mechanism of DHA on ferroptosis in epilepsy. Finally, brain tissue samples from patients with temporal lobe epilepsy (TLE) were collected to validate the expression of ferroptosis‐related markers.

Our experimental results showed that DHA attenuated seizures, hippocampal neuronal damage, and memory and learning deficits in epileptic mice. Moreover, DHA inhibited ferroptosis by activating solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression in vivo and in vitro. Subsequently, we found that DHA activated SIRT1 expression in the mouse hippocampus, leading to a decrease in the acetylation level of forkhead box O1 (FOXO1), thereby increasing the transcriptional activity of SLC7A11. Finally, our findings provide preliminary clinical support for the association between ferroptosis and TLE.

In summary, our findings indicate that DHA may have antiepileptic and neuroprotective benefits by suppressing ferroptosis through the SIRT1/FOXO1/SLC7A11/GPX4 signaling pathway.

Dihydroartemisinin (DHA) is an artemisinin derivative. DHA can alleviate ferroptosis in epileptic mice by activating SIRT1 expression, reducing the acetylation level of FOXO1, and thereby enhancing the transcriptional activity of SLC7A11. DHA shows promise as a new treatment for epilepsy.