--- - |2- Echinacoside (ECH) could attenuate diethylnitrosamine‐induced hepatocellular carcinoma (HCC) in mice, and exerted antiproliferative and proapoptotic functions on HepG2 HCC cell line. ECH exerted its antitumor activity via decreasing TREM2 expression and phosphoinositide 3‐kinase/AKT signaling. Echinacoside (ECH) is a phenylethanoid glycoside extracted from a Chinese herbal medicine, Cistanches salsa. ECH possesses many biological properties, including anti‐inflammation, neural protection, liver protection, and antitumor. In the current study, we aimed to explore the effects of ECH on hepatocellular carcinoma (HCC) and the underlying mechanisms. The results showed that ECH could attenuate diethylnitrosamine (DEN)‐induced HCC in mice, and exerted antiproliferative and proapoptotic functions on HepG2 HCC cell line. ECH exposure in HepG2 cells dose‐dependently reduced the phosphorylation of AKT (p‐AKT) and enhanced the expression of p21 (a cell cycle inhibitor) and Bax (a proapoptotic protein). Furthermore, ECH significantly suppressed insulin‐like growth factor‐1‐induced p‐AKT and cell proliferation. These data indicated that phosphoinositide 3‐kinase (PI3K)/AKT signaling was involved in the anti‐HCC activity of ECH. Gene set enrichment analysis results revealed a positive correlation between the PI3K pathway and triggering receptors expressed on myeloid cells 2 (TREM2) expression in HCC tissues. ECH exposure significantly decreased TREM2 protein levels in HepG2 cells and DEN‐induced HCC. Furthermore, ECH‐mediated proliferation inhibition and AKT signaling inactivation were notably attenuated by TREM2 overexpression. In conclusion, ECH exerted its antitumor activity via decreasing TREM2 expression and PI3K/AKT signaling. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1880-1888, February 2019. '