Ginseng-derived extracellular vesicles alleviate ulcerative colitis by regulating macrophage glycolytic reprogramming and H3K18la-mediated epigenetic modification

Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options due to adverse effects and variable response rates. Plant-derived extracellular vesicles have emerged as promising therapeutic agents owing to their biocompatibility. Although Panax ginseng exhibits anti-inflammatory properties, the role of ginseng-derived extracellular vesicles (GEs) in UC remains unclear. Methods GEs were isolated and characterized. The therapeutic effects of GEs were evaluated in DSS-induced UC mice. Single-cell RNA sequencing was performed to profile colonic immune cells. In vitro experiments using RAW264.7 macrophages and Caco-2 intestinal epithelial cells were conducted to investigate macrophage polarization, glycolytic metabolism, histone lactylation, and barrier function. Gut microbiota and short-chain fatty acid (SCFA) profiles were analyzed by 16S rRNA sequencing and gas chromatography. Results GEs alleviated DSS-induced colitis symptoms, reduced pro-inflammatory cytokines, restored tight junction proteins, and exhibited good biosafety. Single-cell sequencing revealed that GEs remodeled colonic macrophage subsets, reducing pro-inflammatory Ccl7 + macrophages while increasing Pmepa1 + and Vcam1 + populations, and suppressed glycolytic signatures. In vitro, GEs were internalized by macrophages, inhibited LPS-induced M1 polarization, downregulated GLUT1 and LDHA expression, and reduced ATP and lactate production. Mechanistically, GEs specifically decreased H3K18la enrichment at the IL6, TNFA, and INOS promoters, an effect reversed by exogenous lactate. Additionally, GEs restored gut dysbiosis and elevated levels of propionic, acetic, butyric, and isovaleric acids, which correlated with improved disease phenotypes. Conclusion This study demonstrates that GEs alleviate UC by inhibiting macrophage glycolysis, reducing H3K18la-mediated pro-inflammatory gene expression, protecting the intestinal barrier, and modulating the gut microbiota. These results offer new experimental support for GE-based UC therapy and establish a basis for mechanistic and translational follow-up studies.