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Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) has been proven to\u00a0play a\u00a0neuroprotective\u00a0role in TBI, but little is known about the effects of H<jats:sub>2<\/jats:sub>S on TBI-induced ferroptosis. In addition, it is reported that\u00a0the Wnt signaling pathway\u00a0can\u00a0also\u00a0actively\u00a0regulate ferroptosis. However, whether H<jats:sub>2<\/jats:sub>S 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, H<jats:sub>2<\/jats:sub>S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H<jats:sub>2<\/jats:sub>S 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 H<jats:sub>2<\/jats:sub>S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H<jats:sub>2<\/jats:sub>S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H<jats:sub>2<\/jats:sub>S against TBI.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>\n                <jats:p>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.<\/jats:p>","DOI":"10.1007\/s10571-023-01399-5","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T07:02:08Z","timestamp":1692946928000},"page":"4117-4140","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7395-1446","authenticated-orcid":false,"given":"Jie","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0430-8699","authenticated-orcid":false,"given":"Zhennan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6033-2440","authenticated-orcid":false,"given":"Dongyu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4908-2703","authenticated-orcid":false,"given":"Yufei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0593-1966","authenticated-orcid":false,"given":"Xiuli","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1941-9403","authenticated-orcid":false,"given":"Mingxia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-9193","authenticated-orcid":false,"given":"Tong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"1399_CR1","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1038\/s41418-020-00685-9","volume":"28","author":"WD Bao","year":"2021","unstructured":"Bao WD, Pang P, Zhou XT, Hu F, Xiong W, Chen K, Wang J, Wang F, Xie D, Hu YZ, Han ZT, Zhang HH, Wang WX, Nelson PT, Chen JG, Lu Y, Man HY, Liu D, Zhu LQ (2021) Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer\u2019s disease. 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