TREM2: A Potential Target for the Targeted Therapy of Metabolic Diseases

Abstract

Metabolic diseases are characterized by profound dysregulation of the immunometabolic network, in which the interplay between chronic inflammation and metabolic disturbances form a self‐amplifying vicious cycle that drives disease progression. disease progression. Triggering receptor expressed on myeloid cells 2 (TREM2), a central regulator of immunometabolism, interacts with the adaptor protein DAP12 to orchestrate key macrophage functions including polarization, phagocytic clearance, inflammation resolution, and metabolic reprogramming. Through these processes, TREM2 plays a critical role in sensing metabolic stress signals and maintaining immunometabolic homeostasis. In this review, we systematically summarize recent advances in understanding the roles of TREM2 in major metabolic diseases, including atherosclerosis (AS), diabetes mellitus and its complications, obesity, and non‐alcoholic steatohepatitis (NASH), while highlighting its functional heterogeneity across different diseases contexts. We further dissect the regulatory mechanisms governing TREM2 activity, with particular emphasis on cell subset‐specific expression patterns, microenvironmental signal interactions, and post‐translational modifications (PTMs). Moreover, we summarize emerging TREM2‐targeted therapeutic strategies, including soluble TREM2 (sTREM2), agonistic antibodies, and traditional Chinese medicine (TCM)‐based approaches, and evaluate the translational potential of sTREM2 as a noninvasive biomarker. Emerging research frontiers involving TREM2, such as the gut microbiota–metabolism axis and interorgan communication, are also discussed. Finally, we identify key unresolved questions and future research priorities, providing a theoretical framework and potential strategies for precision diagnosis and targeted intervention in metabolic diseases.