H4K12 lactylation drives TREM2high macrophages differentiation in liver fibrosis

BACKGROUND AND AIMS: TREM2-expressing scar-associated macrophages (SAMs) are integral to the pathogenesis of hepatic fibrosis; however, the limited understanding of their differentiation and pro-fibrotic functions impedes the advancement of targeted therapeutic strategies. APPROACH AND RESULTS: Integrated multi-omics analysis, including transcriptomics, 4D proteomics, CUT&Tag, and WGCNA of human and mouse fibrotic livers, coupled with single-cell RNA sequencing, identified SAMs with high TREM2 expression as key drivers of fibrosis. These TREM2high macrophages serve as essential mediators for the reception and transmission of TGF-β signaling. In the context of a fibrotic microenvironment, TGF-β activates HIF-1α-mediated glycolysis and lactate production, leading to an increase in histone lactylation, particularly the p300-catalyzed lactylation of histone H4 at lysine 12 (H4K12la). Importantly, the enrichment of H4K12la at the TREM2 promoter facilitates an upregulation of TREM2 transcription, thereby promoting the differentiation of monocytes into the pro-fibrotic TREM2high macrophage phenotype. Furthermore, the TREM2 protein directly interacted with lactate dehydrogenase A (LDHA), stabilizing its expression and reinforcing lactate production, thereby establishing a complete TREM2/LDHA/H4K12la positive-feedback loop that promotes the differentiation of TREM2high macrophages. In murine models, the knockout of TREM2, macrophage-specific knockdown, and overexpression all disrupted this regulatory loop, inhibited glycolysis and H4K12la modification, and ultimately mitigated liver fibrosis. CONCLUSIONS: H4K12 lactylation facilitates the differentiation of monocytes into TREM2high macrophages within the context of liver fibrosis. This lactylation event enhances and maintains a crucial TREM2/LDHA positive-feedback loop. Intervening in this H4K12la-TREM2 pathway significantly mitigates liver fibrosis, thus presenting a novel potential target for therapeutic intervention in hepatic fibrogenesis.