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This study reports that chronic oxidative stress disrupts gut microbiota and metabolite balance and that such imbalance is intricately tied to the perturbation of Asp metabolism. Under normal conditions, in vivo and in vitro studies reveal that exogenous Asp improves intestinal health by regulating epithelial cell proliferation, nutrient uptake, and apoptosis. During oxidative stress, Asp reduces\n                    <jats:italic>Megasphaera<\/jats:italic>\n                    abundance while increasing\n                    <jats:italic>Ruminococcaceae<\/jats:italic>\n                    . This reversal effect depends on the enhanced production of the antioxidant eicosapentaenoic acid mediated through Asp metabolism and microbiota. Mechanistically, the application of exogenous Asp orchestrates the antioxidant responses in enterocytes via the modulation of the RIP3\u2010MLKL and RIP1\u2010Nrf2\u2010NF\u2010\u03baB pathways to eliminate excessive reactive oxygen species and maintain mitochondrial functionality and cellular survival. These results demonstrate that Asp signaling alleviates oxidative stress by dynamically modulating the gut microbiota and RIP\u2010dependent mitochondrial function, providing a potential therapeutic strategy for oxidative stress disease treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202404697","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T13:01:07Z","timestamp":1738069267000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Aspartate Metabolism\u2010Driven Gut Microbiota Dynamics and RIP\u2010Dependent Mitochondrial Function Counteract Oxidative Stress"],"prefix":"10.1002","volume":"12","author":[{"given":"Shunshun","family":"Jin","sequence":"first","affiliation":[{"name":"Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation Hunan international joint laboratory of Animal Intestinal Ecology and Health Laboratory of Animal Nutrition and 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