Cannabidiol alleviates ferroptosis after traumatic brain injury via the miR3203p/Negr1/ERK signaling axis

<p indent="0mm">Traumatic brain injury (TBI) can cause severe neurological damage. Ferroptosis, a recently discovered form of iron-regulated cell death, is closely associated with TBI. Cannabidiol (CBD) has been demonstrated to exhibit neuroprotective effects. However, the antiferroptotic role of CBD in TBI remains unclear. Investigating whether CBD inhibits ferroptosis after brain injury and its underlying mechanisms is of great significance. We find that ferroptosis can be induced in rats after TBI, and CBD significantly inhibits ferroptosis in TBI rats both <italic>in vivo</italic> and <italic>in vitro</italic>. MicroRNAs (miRNAs) are highly expressed in the brain. Differentially expressed miRNAs and mRNAs after TBI are detected by RNA sequencing, and miR-320-3p, Negr1, and the ERK/MEK pathway are screened out due to their strong correlations. The results show that CBD inhibits miR-320-3p expression, increases Negr1 expression, and suppresses the ERK/MEK pathway both <italic>in vivo</italic> and <italic>in vitro</italic>. Mechanistically, transfection with miR-320-3p mimics or siNegr1 inhibits the intervention effect of CBD on ferroptosis and the ERK/MEK pathway. Additionally, <italic>Negr1</italic> gene silencing reverses the effect of the miR-320-3p inhibitor on ferroptosis factors in PC12 cells, which suggests that miR-320-3p can target <italic>Negr1</italic>. In conclusion, our findings indicate that CBD can inhibit TBI-induced ferroptosis through the miR-320-3p/Negr1/ERK signaling axis.