# MSC-Exosomes alleviate cognitive impairment after mild traumatic brain injury by inhibiting ferroptosis via PI3K/AKT/mTOR-mediated upregulation of GPX4

## TL;DR

This study shows that exosomes from stem cells can help reduce brain damage and cognitive issues after mild traumatic brain injury by stopping a type of cell death called ferroptosis.

## Contribution

The study reveals a novel mechanism by which MSC-Exosomes inhibit ferroptosis via the PI3K/AKT/mTOR pathway to improve cognitive outcomes in mTBI.

## Key findings

- MSC-Exosomes improved cognitive function and reduced lipid peroxidation in mTBI rats.
- MSC-Exosomes restored GPX4 expression and inhibited ferroptosis.
- Transcriptomic analysis showed PI3K/AKT/mTOR pathway activation by MSC-Exosomes.

## Abstract

Mild traumatic brain injury (mTBI) is a prevalent condition accounting for over 70% of all traumatic brain injury (TBI) cases, and it is a major cause of posttraumatic cognitive impairment. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been implicated in the pathophysiology of mTBI. However, its precise role in mTBI - induced cognitive dysfunction and potential therapeutic strategies remain unclear. This study aimed to investigate the neuroprotective effects of mesenchymal stem cell - derived exosomes (MSC - Exos) against ferroptosis and cognitive dysfunction following mTBI. We established an mTBI rat model and administered MSC - Exos at different doses. Behavioral assessments, histological and molecular biological analyses, and bioinformatics approaches were used. The results showed that mTBI rats exhibited cognitive impairments, increased lipid peroxidation, and reduced GPX4 expression. MSC - Exos treatment improved cognitive function in a dose - dependent manner, attenuated lipid peroxidation, and restored GPX4 expression. Transcriptomic and bioinformatic analyses revealed that MSC - Exos activated the PI3K/AKT/mTOR signaling pathway, which upregulated GPX4 expression and inhibited ferroptosis. In conclusion, MSC - Exos alleviate cognitive deficits after mTBI by inhibiting ferroptosis via PI3K/AKT/mTOR - mediated upregulation of GPX4, providing a novel therapeutic strategy for mTBI.