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This study aimed to identify non-chelating polyphenols capable of mitigating zinc toxicity and to elucidate their protective mechanisms, with emphasis on ferroptosis inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network toxicology predicted ferroptosis as a central mechanism in zinc-induced intestinal injury, which was confirmed in intestinal epithelial cells where zinc overload specifically induced ferroptosis without activating apoptosis, necroptosis, or autophagy. From multiple polyphenols, fisetin (FIS) was identified as a non-chelating candidate that alleviated zinc-induced cytotoxicity, preserved tight junction proteins, and activated the Nrf2-GPX4 axis to inhibit ferroptosis in vitro. In zinc-overloaded weaned piglets, FIS supplementation maintained the growth-promoting effects of high-dose zinc while ameliorating intestinal damage. FIS also attenuated oxidative stress, alleviated inflammation, and inhibited ferroptosis in the jejunum. Furthermore, FIS remodeled the gut microbiota, enriching beneficial taxa\n                      <jats:italic>Romboutsia<\/jats:italic>\n                      (positively correlated with growth performance) and\n                      <jats:italic>Clostridium_sensu_stricto_1<\/jats:italic>\n                      (positively correlated with the p-Nrf2\/Nrf2 ratio), while suppressing the zinc-enriched\n                      <jats:italic>Anaerovibrio<\/jats:italic>\n                      (negatively correlated with GPX4 protein expression). FIS also shifted microbial metabolic pathways toward amino acid and terpenoid metabolism, potentially contributing to the observed ferroptosis defense.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>FIS alleviates high-dose ZnO-induced intestinal injury in weaned piglets through dual modulation, activating the Nrf2-GPX4 axis to inhibit ferroptosis and remodeling the gut microbiota to reinforce this defense. By preserving the growth benefits of zinc while mitigating its toxicity, FIS represents a promising nutritional strategy for sustainable swine production.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40104-026-01481-0","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T23:01:22Z","timestamp":1786230082000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fisetin alleviates zinc overload-induced intestinal injury by inhibiting ferroptosis and remodeling gut microbiota in weaned piglets"],"prefix":"10.1186","volume":"17","author":[{"given":"Feifei","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huangen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2690-429X","authenticated-orcid":false,"given":"Jie","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,9]]},"reference":[{"key":"1481_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.883107","volume":"12","author":"WF Su","year":"2022","unstructured":"Su WF, Gong T, Jiang ZP, Lu ZQ, Wang YZ. 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