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 in vivo and in vitro studies using a controlled cortical impact (CCI) model. We observed that Tyro3 knockdown exacerbated ferroptosis, while Tyro3 overexpression mitigated it. Moreover, treatment with the Tyro3 agonist Gal-3 conferred protective effects, improving both motor and cognitive functions through Tyro3 activation. These results highlight Tyro3 as a promising therapeutic target for TBI.