β‐Elemene Rescues Radiation‐Induced Enteritis by Orchestrating a Host‐Microbiome Circuit That Fuels Epigenetic DNA Repair

ABSTRACT Radiation‐induced enteritis (RIE) is a severe, dose‐limiting toxicity of cancer radiotherapy lacking mechanism‐based therapies. While the gut microbiome regulates radiation injury, harnessing it therapeutically remains challenging. Here, we show that the natural product β‐elemene protects against RIE through a synergistic mechanism coordinating host and microbial responses. β‐elemene directly rescues the radiation‐disrupted interaction between the lactate transporter MCT1 and its chaperone CD147 in intestinal epithelial cells, priming them for enhanced lactate uptake. Concurrently, β‐elemene selectively enriches for Lactobacillus gasseri , increasing intestinal lactate production. The convergence of host priming and elevated lactate availability triggers a metabo‐epigenetic cascade. Specifically, lactate drives the lactylation of the chromatin‐associated protein RBBP4, which in turn recruits EP300 to activate the transcription of essential DNA damage repair genes. We further identify EP300 as a lactyl‐transferase, establishing a self‐amplifying positive feedback loop that robustly enhances the repair signal. Our findings delineate a complete drug‐microbe‐metabolite‐epigenome axis, establishing a ‘prime‐and‐fuel’ therapeutic strategy where a single agent orchestrates inter‐kingdom communication to promote tissue regeneration.