Exploring the role of lipied metabolism in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive cancer with poor survival rates and limited treatment options whose prevalence is expected to increase up to 137% by 2030. Existing therapies outside of liver resection or transplantation have poor efficacy, and few new treatment options have been developed in recent decades. It is known that the lipid metabolism of HCC cells is significantly altered relative to normal liver cells, often involving upregulation of fatty acid synthesis and oxidation enzymes. Targeting these lipid metabolic enzymes could represent a class of novel therapeutic methods for the treatment of HCC. To investigate this possibility, we assembled a targeted library of lipid metabolic drugs and clinical compounds for a repurposing screen. We treated two liver cancer cell lines with 187 compounds targeting a diverse range of lipid metabolic enzymes in order to determine their relative anti-proliferative effects and possible therapeutic potential. Putative hit compounds were further investigated by dose response analyses and metabolic profiling by mass spectrometry. The most efficacious compounds were those identified to be targeting enzymes involved in lipid-based signaling molecule synthesis, suggesting that increased cell signaling may be a mechanism supporting enhanced proliferation downstream of lipid metabolic enzyme upregulation in HCC.