Previous reports have demonstrated that SIRT1 can deacetylate and activate the AKT pathway (123), and USP22 can promote MDR in HCC cells by activating the SIRT1/AKT/MRP1 pathway (124); USP22 is also able to regulate chemotolerance in HCC through Smad4/Akt-dependent MDR-related gene regulation (117). Here, SMAD4 is linked to hepatocellular carcinoma.