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. Graphical Abstract 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.

Long non‑coding RNA lung cancer‑associated transcript 1 regulates ferroptosis via microRNA‑34a‑5p‑mediated GTP cyclohydrolase 1 downregulation in lung cancer cells

“…2E ). Additionally, KEGG pathway analysis revealed that the 'MAPK signaling pathway' ( 51 , 52 ), 'Hippo signaling pathway' ( 53 ) and 'Wnt signaling pathway' ( 54 ) were enriched ( Fig. 2F ), suggesting that DElncRNAs are involved in ferroptosis.…”

Innovative Insights into Traumatic Brain Injuries: Biomarkers and New Pharmacological Targets

“…H 2 S has emerged as a prospective therapeutic agent, with anti-ferroptotic properties, enhancing brain function recovery following a TBI. Notably, the Wnt signaling pathway was significantly reduced after controlled cortical impact in mice, and its activation might be crucial in the neuroprotective effects associated with H 2 S in the context of TBIs [105]. Anacardic acid has also shown promise in alleviating neurological and behavioral cognitive impairments from TBIs via the dual effect of anti-ferroptosis and anti-inflammation [106].…”

“…Inhibition of ferroptosis may have been induced by H 2 S, perhaps via the Wnt/β-catenin pathway. [105] Weightdrop model…”