# Ferroptosis‐Mediated Hippocampal Neuronal Loss Post‐mTBI: Chromatin Accessibility Profiling and Single‐Nucleus Transcriptomics

## TL;DR

This study finds that a type of cell death called ferroptosis causes hippocampal neuron loss after mild brain injury, and identifies a gene that could help protect neurons.

## Contribution

The study identifies ferroptosis as a key driver of neuronal death in mTBI and uncovers Tmsb4x as a novel therapeutic target.

## Key findings

- Ferroptosis is the dominant cell-death pathway in hippocampal neurons after mTBI.
- The gene Tmsb4x protects neurons by downregulating Slc2a2 and counteracting ferroptosis.
- Reduced binding of c-Jun and Rfx3 in dentate granule cells correlates with neuronal vulnerability.

## Abstract

Neuronal death in the hippocampus following mild traumatic brain injury (mTBI) is a hallmark of cognitive dysfunction, yet the underlying molecular mechanisms remain poorly understood. To address this issue, the hippocampus of eCCI‐modeled mTBI mice is profiled using single‐nucleus RNA‐seq and ATAC‐seq, producing matched, cell‐type‐resolved transcriptomic and chromatin‐accessibility datasets. Gene sets covering major cell‐death pathways are curated and scored for their activity across neuronal subtypes. Ferroptosis emerged as the dominant program. Gene‐set enrichment indicated activation of mitochondrial damage‐related pathways in neurons, a hallmark of ferroptosis. Transcription‐factor analyses, supported by epigenetic data, showed decreased binding of c‐Jun and Rfx3 in dentate granule cells. Functional assays show that the c‐Jun‐regulated gene Tmsb4x protects hippocampal neurons after mTBI. It downregulates Slc2a2, counteracts ferroptosis, and is associated with improved motor and cognitive performance in mice. This study advances understanding of mTBI pathogenesis at single‐cell resolution, identifying ferroptosis as a critical determinant of neuronal death and uncovering Tmsb4x as a promising therapeutic target for mitigating cognitive dysfunction.

Hippocampal single ‐nucleus transcriptomes and chromatin accessibility after mild traumatic brain injury reveal dentate granule neuron vulnerability driven by ferroptosis. The c‐Jun–Tmsb4x–Slc2a2 axis modulates lipid peroxidation and iron dysregulation. Functional assays—including ChIP‐qPCR, in vitro ferroptosis rescue, and TEM—corroborate mechanisms and highlight Tmsb4x/Tβ4 as potential neuroprotective avenues.