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

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.