Hepatocellular Carcinoma Overcomes Lipid Depletion by Utilizing Serine for Phospholipid Synthesis and Enhanced Survival

Abstract

Abstract Metabolic vulnerabilities of hepatocellular carcinoma (HCC) remain largely unexplored, though deregulation in these processes is a hallmark of cancer. HCC cells exhibit a marked dependence on lipids and have distinct responses to lipid depletion. Challenging HCC cells phenotype by lipid depletion, we studied their reaction through functional assays, lipidomic, metabolic, transcriptomic profiles, and metabolic fluxes. HCC cell lines were grouped as lipid-depletion sensitive (LD-S), characterized by high triglycerides and cholesterol esters, or resistant (LD-R), marked by increased membrane lipids like phosphatidylcholine and phosphatidylethanolamine. LD-R cells showed serine uptake and carbon-donor incorporation into lipid synthesis pathways during lipid depletion. A distinct 150-gene lipid-associated signature differentiated HCC patients into subtypes, correlating LD-R traits with lower survival, higher vascular invasion, and distinct immune compositions, including associating Kupffer cells to LD-S tumors. This sensitivity to lipid depletion underscores lipid metabolism as a therapeutic target, potentially offering new treatments for HCC patients.