Mus musculus breed:C57BL/6 Transcriptome or Gene expression. Mus musculus breed:C57BL/6

p62/SQSTM1 is a ubiquitin-binding autophagy receptor and signaling protein thataccumulates in premalignant liver diseases and most hepatocellular carcinomas (HCC). Although p62was proposed to participate in formation of benign adenomas in autophagy-deficient livers, its role inHCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC inductionin mice and that its high expression level in non-tumor human liver predicts rapid HCC recurrence aftercurative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, c-Myc inductionand protection of HCC-initiating cells from oxidative stress-induced death.