Unveiling the Dual Expression of Haptoglobin in Malignant Hepatocellular Carcinoma Cells through Single-Cell and Bulk RNA Sequencing Analysis

Abstract Hepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer. Existing single-cell transcriptome research on HCC mainly focuses on immune and stromal cells, with limited analysis of malignant cell heterogeneity. In our study, we identified the key subgroup (subgroup 6) of HCC malignant cells with conflicting survival outcomes, and found haptoglobin (HP) as the key gene. Our analysis suggests that HP plays a tumor suppressive role in malignant cells, but has a negative correlation with immunity. Down-regulation of HP expression in HCC immune cells promotes Th1 cell-associated markers expression and reduces the differentiation of Th2 cells to Th1 cells, indirectly suppressing tumor growth. In malignant cells, up-regulation of HP expression to inhibit tumors is associated with the expression of malignant genes. At the same time, the up-regulation of HP expression in Pyridoxine inhibition of HCC is related to Metabolic pathways, Complement and coagulation cascades, Metabolism of xenobiotics by cytochrome P450, Retinol metabolism, Drug metabolism - cytochrome P450, Drug metabolism - other enzymes, Chemical carcinogenesis - DNA adducts, Bile secretion, and Biosynthesis of cofactors. Our study identified HP, a tumor suppressor gene in the malignant cell subpopulation of HCC, which exerts tumor suppressive effects through different mechanisms in immune cells and malignant cells, providing a new reference for the clinical treatment of HCC.