We propose a novel strategy to enhance proteotoxic stress in HCC but with less toxic side effects on non-cancer cells by combining the pan-cyclophilin inhibitor rencofilstat (RCF, non-immunosuppressive analog of cyclosporin A, formerly known as CRV431) [21,22] and a second-generation UPS inhibitor (ixazomib, Ixz; approved for multiple myeloma) [23,24]. The gene discussed is PPIB; the disease is hepatocellular carcinoma.