Uncovering cellular perturbations and key mediator communications in liver cancer using single-cell RNA sequencing.

Liver cancer ranks as the sixth most common malignancy and the third leading cause of cancer-related death, with hepatocellular carcinoma (HCC) accounting for over 80% of cases. Its aggressive nature and late diagnosis severely limit treatment options. Tumor heterogeneity and a complex immune microenvironment further impede immunotherapy efficacy. By analyzing HCC data, we identified an epithelial subtype marked by proliferative capacity, invasiveness, and metabolic reprogramming, particularly in sugar and lipid metabolism. This subtype contributes to immune microenvironment complexity through interactions with Lipid-Associated tumor associated macrophage cells (LA_TAMs) that are linked to disease progression. A prognostic model (Tumor Epithelial Feature Signature, TEFS) revealed UAP1L1 as a computationally predicted key modulator of the cell cycle and extracellular matrix remodeling. Functional validation confirmed its clinical relevance and oncogenic role. These findings link epithelial features, metabolic dysregulation, and immune dynamics in HCC, identifying UAP1L1 as a potential target to enhance immunotherapy efficacy.