To conclude, we describe for the first time that the cholesterol content of the membrane balances the endocytosis and shedding of CD147 and that sequential intramembrane proteolysis produces nuclear-localized CD147-ICD, which modulates autophagy in HCC cells through the NF-κB–TRAIL–caspase8–ATG3 pathway. The gene discussed is TNFSF10; the disease is hepatocellular carcinoma.