In our study, through integrating single-cell multi-omics data to systematically identify critical metabolic reprogramming-associated gene signatures and verify SF3A3’s function in HCC cells, we found that obvious metabolic heterogeneity exists within tumor epithelial cells, and SF3A3 can serve as a biomarker for diagnosis and prognosis assessment as well as a potential therapeutic target in HCC. This evidence concerns the gene SF3A3 and neoplasm.