Histone lactylation scarring transmits metabolic and epigenetic memory across the gut-liver axis.

Abstract

Ulcerative colitis (UC) remission does not abolish susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanism linking prior intestinal inflammation to delayed liver injury remains unclear. We establish gut-liver axis memory transduction as an epigenetic-cellular-organ cascade in which inflammatory history is molecularly encoded and redeployed across organs. LCN2+ colonic macrophages persist after colitis resolution and retain heightened glycolysis together with durable histone H3K9 L-lactylation (H3K9la). These macrophages maintain a permissive memory state during remission and traffic to the liver, where they amplify steatosis under subsequent HFD challenge. Mechanistically, BRG1 cooperates with CEBPB at H3K9la-marked chromatin to sustain Lcn2 and Pkm transcription in a feed-forward circuit. Myeloid-specific Smarca4 deletion or pharmacological interruption of macrophage trafficking attenuates macrophage memory and protects against MASLD. Together, our findings define H3K9la-centered macrophage memory as a mobile pathogenic imprint that links prior colitis to increased susceptibility to metabolic liver disease.