NEW research has uncovered a molecular pathway that may drive the progression of liver fibrosis, highlighting a potential therapeutic target centred on TREM2-expressing scar-associated macrophages (SAMs).
Liver fibrosis is characterised by the accumulation of scar tissue following chronic liver injury, but the mechanisms that govern the development and activity of fibrosis-associated immune cells remain incompletely understood. In particular, TREM2-expressing macrophages have emerged as key contributors to fibrotic disease, although the processes underlying their differentiation have remained unclear.
Multi-omics in research
Using an integrated multi-omics approach, researchers analysed human and murine fibrotic liver samples through transcriptomics, proteomics, epigenetic profiling, and single-cell RNA sequencing. The analyses identified a population of TREM2^high macrophages as central drivers of fibrosis and key mediators of transforming growth factor beta (TGF-β) signalling within the fibrotic microenvironment.
The study found that TGF-β signalling activated HIF-1α-dependent glycolysis and increased lactate production in macrophages. Elevated lactate levels subsequently promoted histone lactylation, particularly lactylation of histone H4 at lysine 12 (H4K12la). Researchers observed that this epigenetic modification accumulated at the TREM2 promoter, enhancing TREM2 expression and promoting the differentiation of monocytes into pro-fibrotic TREM2^high macrophages.
Further investigation revealed that TREM2 directly interacted with lactate dehydrogenase A (LDHA), stabilising the enzyme and sustaining lactate production. This created a self-reinforcing TREM2/LDHA/H4K12la feedback loop that supported the continued development and maintenance of the pro-fibrotic macrophage population.
The functional importance of this pathway was confirmed in mouse models. TREM2 knockout, macrophage-specific TREM2 knockdown, and TREM2 overexpression experiments all demonstrated that disrupting the feedback loop reduced glycolytic activity, decreased H4K12la modification, and attenuated liver fibrosis.
The findings provide new insight into the metabolic and epigenetic mechanisms underlying hepatic fibrogenesis and identify the H4K12la–TREM2 axis as a potential target for anti-fibrotic therapies. The researchers suggest that interventions aimed at disrupting this feedback loop could offer a novel strategy for limiting fibrosis progression in chronic liver disease.
Reference
Yang F et al. Novel TREM2 Feedback Loop Identified as Driver of Liver Fibrosis. Hepatology. 2026.
Featured image; Adobestock/Amazing studio
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