Unveiling EMC6 as a novel pathogenic determinant in hepatocellular carcinoma: orchestration of lipid metabolism through regulation of lipid droplet-associated enzyme HSD17B13.

The endoplasmic reticulum (ER) membrane protein complex (EMC) is an ER multiprotein complex that affects a wide range of pathophysiological processes. Recently, the function of EMC6, a subunit of EMC, has been attracting attention for its role in cancers. However, research on EMC6 in the context of hepatocellular carcinoma (HCC) remains unknown. Here, we first observed the decreased EMC6 expression in human HCC tissues, and diminished expression level of EMC6 was associated with poor prognosis of HCC patients. In parallel, the knockdown of EMC6 promoted tumor progression both in HCC cell lines and in tumor-cell bearing nude mice. To delineate the in vivo roles of EMC6, we generated a hepatocyte-specific knockout of Emc6 (Emc6;Alb-Cre, named Emc6 LKO) using a floxed Emc6 line. Emc6 LKO mice exhibited progressive liver dysfunction, fibrosis and spontaneous carcinogenesis phenotypes. Significant lipid metabolic disorder in the Emc6 LKO liver was revealed by combined metabolomic and proteomic analysis. Moreover, drastic elevation of 17β-Hydroxysteroid dehydrogenase type 13 (HSD17B13), a lipid droplet-associated enzyme, was identified to be involved in the process of EMC6-induced lipid metabolic disorder and HCC progression. Inhibition of HSD17B13 by a Pharmacological inhibitor BI-3231 effectively mitigated EMC6-driven HCC progression in vitro and in vivo. Taken together, these results unveiled a novel regulatory mechanism of EMC in HCC progression through lipid metabolism and may provide a new biomarker and therapeutic target for HCC.