Gal-3 activates Tyro3 to ameliorate ferroptosis of hippocampal neurons after traumatic brain injury

Traumatic brain injury (TBI) leads to significant hippocampal neuronal loss, contributing to cognitive dysfunction. Our bioinformatics analysis of single-cell RNA sequencing data from hippocampal tissue following TBI revealed persistent neuronal loss and activation of ferroptosis-related pathways. Notably, Tyro3 expression was significantly upregulated, suggesting its potential role in neuronal ferroptosis. This finding was further validated in both <i>in vivo</i> and <i>in vitro</i> studies using a controlled cortical impact (CCI) model. We observed that <i>Tyro3</i> knockdown exacerbated ferroptosis, while <i>Tyro3</i> overexpression mitigated it. Moreover, treatment with the <i>Tyro3</i> agonist Gal-3 conferred protective effects, improving both motor and cognitive functions through <i>Tyro3</i> activation. These results highlight <i>Tyro3</i> as a promising therapeutic target for TBI.