Cell viability analysis using HepG2 cells overexpressing GRP78, delATPase or delPBD indicated that overexpression of GRP78 or its delPBD resulted in a pronounced resistance to 5-FU; By contrast, HepG2 cells overexpressing delATPase significantly increased the sensitivity of HepG2 cells to 5-FU, demonstrating that GRP78 could cause the resistance to 5-FU through its ATPase domain in HCC. Here, HSPA5 is linked to hepatocellular carcinoma.