Atypical Sphingolipids in healthy and diseased liver

About This Grant

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death and is closely linked to liver metabolic dysfunction. While the liver’s role in metabolism is well established, how metabolic changes contribute to HCC remains poorly understood. Bioactive sphingolipids (SLs), including ceramide and sphingosine-1-phosphate, are critical regulators of cell metabolism in numerous contexts. While the first committed step in SL synthesis is catalyzed by serine palmitoyltransferase (SPT) typically composed of Sptlc1 and Sptlc2 subunits, we recently found that under pathological conditions, a novel subunit, Sptlc3 replaces Sptlc2, producing atypical sphingolipids with largely unknown functions. Sptlc3 is induced in human HCC, liver cancer cell lines, and mouse models of liver disease and cMyc-driven HCC. Preliminary and recently published data from our laboratory show that Sptlc3-derived lipids regulate key metabolic pathways in hepatocytes, including oxidative phosphorylation, gluconeogenesis, and the TCA cycle. Importantly, inhibiting Sptlc3 selectively reduces viability in cancer cells without affecting normal liver cells. This suggests that Sptlc3 may be a novel therapeutic target in HCC by disrupting cancer-specific metabolic dependencies. We will explore this possibility in three aims: Aim 1: We will determine the scope of metabolic regulation by Sptlc3 in hepatocytes, including its effects on energy metabolism, mitochondrial function, mitophagy, and NAD⁺-dependent metabolic rewiring through sirtuin deacetlyases. Aim 2: We will identify the subset of cMyc-driven metabolic rewiring that is mediated by Sptlc3 using metabolomics and spatial transcriptomics. And Aim 3: We will evaluate the therapeutic potential of targeting Sptlc3 genetically and pharmacologically in a cMyc-driven mouse model of HCC. Together, these studies will define the role of Sptlc3 in liver cancer metabolism and assess its viability as a therapeutic target. The findings could uncover new metabolic vulnerabilities in HCC and support the development of first-in-class Sptlc3 inhibitors. Importantly, the translational potential of these studies will require the mouse experiments to test the impact of the novel compounds on complexities of tumor biology including size, number, location, microenvironment, metastasis, and other features for which an in vivo environment is required to mimic the situation of human HCC. Mice are also required to determine pharmacokinetic parameters, which result from a complex interplay between tissues, the circulation, and distal organs including kidney, which plays a major role in drug detoxification and secretion.