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Nanozymes possess higher stability, are more economical, and have more multifunctionalities than natural enzymes and thus could be an ideal approach for their combination. Therefore, this study synthesised a nanozyme using glutathione (GSH) and Se\u2014GSH-Se\u2014and evaluated its alleviating effects on colitis in mice induced by dextran sulphate sodium salt (DSS). Three doses of GSH-Se, 6 mM, 12 mM, and 18 mM were supplemented in DSS-induced colitis in mice. Findings showed that GSH-Se supplementation ameliorated colitis by improving the colonic mucosal integrity, reducing inflammatory responses and oxidative stress, and alleviating gut microbiota imbalance in mice with DSS-induced colitis. Moreover, an in vitro experiment was performed to unravel the molecular mechanism by which GSH-Se ameliorated colitis in mice, based on lipopolysaccharide-induced inflammation in mouse colon epithelial cells. The results suggested that the alleviating effects of GSH-Se on mouse colitis was likely mediated by the activation of the Nrf2\/Keap1 (nuclear factor E2-related factor 2\/Kelch-like ECH-associated protein 1) and GPx4 signalling pathways.<\/jats:p>","DOI":"10.3390\/ijms26051866","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T10:12:11Z","timestamp":1740132731000},"page":"1866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Novel Selenium-Based Nanozyme (GSH-Se) Ameliorates Colitis in Mice by Modulating the Nrf2\/Keap1 and GPx4 Pathways"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8437-0073","authenticated-orcid":false,"given":"Caimei","family":"Wu","sequence":"first","affiliation":[{"name":"Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Key Laboratory of Animal Disease-Resistance 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