YTHDF1-modified neural stem cells confer neuroprotection and promote functional recovery following traumatic brain injury.

Traumatic brain injury (TBI) is a significant contributor to global morbidity and mortality, with limited effective treatment options available. Neural stem cells (NSCs) have shown great potential in the treatment of TBI. However, the relatively low differentiation rate of neurons largely hinders the therapeutic efficacy of brain tissue repair. Here, we found that following TBI, the expression level of YTHDF1 in the hippocampus significantly increased and then decreased. Previous reports have also indicated that YTHDF1 mRNA is preferentially expressed in the mouse hippocampus, a key region involved in spatial learning and memory. Subsequently, we overexpressed or knocked down YTHDF1 in NSCs, and the results demonstrated that YTHDF1 promoted NSC proliferation and neuronal differentiation. In vitro, neuronal injury was induced by H2O2, and co-cultured with YTHDF1-modified NSCs to assess neuronal cell viability, apoptosis, and oxidative stress biomarkers, including the activities of superoxide dismutase (SOD) and catalase (CAT). YTHDF1-modified NSCs significantly reduced neuronal apoptosis and lowered oxidative stress levels. The expression of YTHDF1 in the hippocampus of TBI mice could rescue sensory, motor, and cognitive deficits, promoting neuronal survival. Mechanistically, YTHDF1 may be transcriptionally regulated by MYCN, and exert neuroprotective effects through the PI3K/AKT signaling pathway.