Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway.

Abstract

Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H₂S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H₂S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H₂S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H₂S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H₂S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H₂S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H₂S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H₂S against TBI. TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway.