Dynamic Crosstalk Between TREM2⁺ Macrophages and the MASLD Hepatic Microenvironment

Chronic liver disorders, including metabolic/alcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, have complex pathogenesis in which triggering receptor expressed on myeloid cells 2 (TREM2) has an important role. In metabolic dysfunction-associated steatotic liver disease (MASLD), TREM2 is detectable in several hepatic non-parenchymal cell types, including Kupffer cells and hepatic stellate cells, but is most highly expressed in recruited monocyte-derived macrophages. TREM2 regulates macrophage lipid handling, inflammatory responses, and phagocytosis. TREM2⁺ macrophages are heterogeneous, and their functions vary with disease stage and local microenvironment. TREM2 has emerged as a therapeutic target in neurological diseases, while soluble TREM2 is being investigated as a noninvasive biomarker in MASLD. However, no TREM2-targeted therapy has yet been developed for MASLD. A clearer understanding of TREM2 signaling during progression from steatosis to metabolic dysfunction-associated steatohepatitis(MASH), hepatic fibrosis (HF), and hepatocellular carcinoma(HCC) may help identify new therapeutic strategies.