p62/Sqstm1 is a multifunctional protein involved in cell survive, growth and death and degraded by autophagy.Phosphorylation of p62/Sqstm1 at Ser351 causes inactivation of Keap1, an adaptor of the Cul3-ubiquitin ligase complex responsible for degrading a transcription factor,Nrf2.The phosphorylated p62/Sqstm1 accumulates in autophagy-deficient mouse liver tumor and human hepatocellular carcinoma (HCC), which assists their growth depending on Nrf2-activation.However, the molecular mechanism how the p62-Keap1-Nrf2 axis provides tumor cells with proliferation potency remains unclear.Herein, we show unique glucose and glutamine metabolisms in autophagy-defective mouse livers and HCC cells harboring S351-phosphorylated p62/Sqstm1 and demonstrate their effects on anti-cancer drug tolerance as well as tumor growth.