ICMT deficiency ameliorates weight loss and mortality, but not tumor formation in a mouse model of liver cancer

Liver cancer often arises in the setting of chronic liver disease and remains a major global health challenge with limited effective treatments. Isoprenylcysteine Carboxyl Methyltransferase (ICMT) is an enzyme that catalyzes the methylation of prenylated proteins containing a CAAX motif, such as RAS, a modification thought to be essential for their function. Given its role in oncogenic signaling, ICMT has emerged as a potential therapeutic target in cancer. Notably, ICMT is overexpressed in human hepatocellular carcinoma (HCC), and previous studies have shown that Icmt deletion impairs BrafV600E-driven transformation in murine fibroblasts. In this study, we investigated the role of ICMT in liver cancer using a genetically engineered mouse model with hepatocyte-specific expression of BrafV600E, combined with deletion of Trp53 and Icmt. We assessed the impact of Icmt loss on liver physiology, tumorigenesis, and global transcriptomic and proteomic landscapes. Expression of BrafV600E led to progressive body weight loss, reduced survival, hepatomegaly, vascular congestion, liver fibrosis, and tumor development. These phenotypic changes were associated with widespread alterations in gene and protein expression, particularly affecting pathways related to cell differentiation, coagulation, and metabolism. Strikingly, liver-specific Icmt deletion ameliorated several pathological features, including weight loss, early mortality, fibrosis, and vascular abnormalities. It also partially normalized the transcriptomic and proteomic profiles. However, Icmt deletion did not prevent hepatomegaly or tumor formation. In conclusion, while ICMT inhibition mitigates several deleterious effects of BrafV600E-driven liver pathology, it does not block tumorigenesis. These findings suggest that ICMT is not a suitable therapeutic target for liver cancer prevention or treatment, but may have potential as a target to alleviate liver disease-associated symptoms.