Metabolomic and lipidomic analyses reveal phosphatidylcholine-lysophosphatidylcholine axis alterations in sorafenib-persistent hepatocellular carcinoma.

Metabolic reprogramming and lipid remodeling are increasingly recognized as key processes underlying carcinogenesis and cancer treatment failure. The liver, as a central hub for lipid metabolism and homeostasis, is particularly susceptible to such alterations. Accordingly, hepatocellular carcinoma (HCC) exhibits extensive metabolic dysregulation and lipid remodeling, contributing to resistance to systemic therapies, including sorafenib. This study characterized histopathological and metabolic signatures across HCC carcinogenesis stages using a diethylnitrosamine/thioacetamide-induced rat model. Histopathological analysis confirmed gradual progression from inflammation to cirrhosis and finally HCC, based on non-alcoholic fatty liver disease activity scoring and non-alcoholic steatohepatitis fibrosis staging. Metabolomic profiling revealed stage-specific metabolic patterns throughout disease progression, with a marked shift toward lipid-centric metabolism during fibrosis and in sorafenib-persistent tumors, defined here as cancer cells that survive sorafenib treatment. These metabolic changes highlight the role of lipid remodeling in both early carcinogenesis and systemic treatment tolerance. Furthermore, lipidomic analysis of sorafenib-persistent HCC demonstrated significant accumulation of lysophosphatidylcholine (LPC)(20:4) and depletion of precursor phosphatidylcholine species, demonstrating alterations to the phosphatidylcholine-lysophosphatidylcholine axis. Given that cytosolic phospholipase A2 (cPLA2) is a key enzyme that hydrolyzes phosphatidylcholine to generate lysophosphatidylcholine, we hypothesized that cPLA2 may contribute to the observed lipid imbalance. Mechanistic validation in sorafenib-treated HepG2 cells using the cPLA2 inhibitor AACOCF3 showed increased sorafenib sensitivity, enhanced apoptosis, and reduced clonogenicity upon cPLA2 inhibition. Collectively, these findings identify phosphatidylcholine-lysophosphatidylcholine axis alteration as a potential driver of cancer cell survival under sorafenib treatment and highlight lipid metabolic reprogramming as a sorafenib-re-sensitization target in HCC.