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While the gut microbiome regulates radiation injury, harnessing it therapeutically remains challenging. Here, we show that the natural product \u03b2\u2010elemene protects against RIE through a synergistic mechanism coordinating host and microbial responses. \u03b2\u2010elemene directly rescues the radiation\u2010disrupted interaction between the lactate transporter MCT1 and its chaperone CD147 in intestinal epithelial cells, priming them for enhanced lactate uptake. Concurrently, \u03b2\u2010elemene selectively enriches for\n                    <jats:italic>Lactobacillus gasseri<\/jats:italic>\n                    , increasing intestinal lactate production. The convergence of host priming and elevated lactate availability triggers a metabo\u2010epigenetic cascade. Specifically, lactate drives the lactylation of the chromatin\u2010associated protein RBBP4, which in turn recruits EP300 to activate the transcription of essential DNA damage repair genes. We further identify EP300 as a lactyl\u2010transferase, establishing a self\u2010amplifying positive feedback loop that robustly enhances the repair signal. Our findings delineate a complete drug\u2010microbe\u2010metabolite\u2010epigenome axis, establishing a \u2018prime\u2010and\u2010fuel\u2019 therapeutic strategy where a single agent orchestrates inter\u2010kingdom communication to promote tissue regeneration.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521445","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:15:51Z","timestamp":1779894951000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b2\u2010Elemene Rescues Radiation\u2010Induced Enteritis by Orchestrating a Host\u2010Microbiome Circuit That Fuels Epigenetic DNA Repair"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiancheng","family":"He","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery Affiliated Hospital and Medical School of Nantong University  Nantong China"},{"name":"Department of General Surgery Binhai 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