INTRODUCTION: Metabolic steatotic liver disease (MASLD) can progress to hepatocellular carcinoma (HCC). 25% of MASLD-HCCs occur in the absence of fibrosis. OBJECTIVES: This study aimed to explore lipid metabolic pathways through "omics" and to identify biomarkers of MASLD-HCC based on the degree of fibrosis. METHODS: Our cohort included 79 pairs of MASLD-HCC tumor tissues (TT) and adjacent non-tumor human liver tissues (NTT), which were divided into two groups according to fibrosis degree (F0F2 n = 45 and F3F4 n = 34). Lipidomic analysis (n = 52) using liquid chromatography high-resolution mass spectrometry (LC-HRMS/MS) and gene expression analysis (n = 79) using RT-qPCR were performed. For each group, TT was compared with NTT. Five healthy liver tissues were used as calibrators in gene expression analysis. RESULTS: Using LC-HRMS/MS, 130 lipids were putatively annotated, 30 of which showed a significant difference between TT and NTT. In MASLD-HCC-F0F2, ceramide levels decreased. While sphingomyelin, most phosphatidylcholine and phosphatidylethanolamine species were increased. In contrast, in MASLD-HCC-F3F4, most lipid contents decreased. Based on lipidomic data, a panel of 18 genes related to lipid metabolism was analyzed. The expression of six genes, ACAT2, DGAT2, ACOX1, CHKA, PLD1, and PLD2, was exclusively upregulated in MASLD-HCC-F0F2. Taken together, these data support the existence of two MASLD-HCC lipid metabolic phenotypes, according to the degree of fibrosis. CONCLUSION: In conclusion, our results allow: (1) discriminate two phenotypes of MASLD-HCC according to fibrosis level
(2) propose PLD as a potential drug target for MASLD-HCC-F0F2 patients, and suggest that PLD inhibitor could be evaluated in combination with immunotherapy treatment.