New research has identified a molecular pathway that may drive liver fibrosis progression, highlighting a potential therapeutic target centered on TREM2-expressing scar-associated macrophages.
Using integrated multi-omics analysis of human and murine fibrotic liver samples, researchers identified TREM2-high macrophages as central drivers of fibrosis and key mediators of TGF-β signaling.
The study found TGF-β signaling activates glycolysis and increases lactate production in macrophages. Elevated lactate promotes histone lactylation at the TREM2 promoter, enhancing TREM2 expression and promoting differentiation of monocytes into pro-fibrotic macrophages.
TREM2 directly interacts with lactate dehydrogenase A, stabilizing the enzyme and sustaining lactate production. This creates a self-reinforcing TREM2/LDHA/H4K12la feedback loop that maintains the pro-fibrotic macrophage population.
Functional importance was confirmed in mouse models. Disrupting the feedback loop reduced glycolytic activity, decreased histone modification, and attenuated liver fibrosis.
The findings identify the H4K12la-TREM2 axis as a potential target for anti-fibrotic therapies, offering a novel strategy for limiting fibrosis progression in chronic liver disease.
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