To elucidate the principal downstream mediator responsible for USP18-mediated Sorafenib resistance in HCC, we conducted cluster analysis on the differential protein expression based on the whole-proteome analysis of HepG2 cells with or without overexpression of USP18 (HepG2-USP18-OE vs. HepG2-Ctrl), we identified 47 commonly downregulated proteins and 31 upregulated proteins .