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

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.