The NOTCH1 signaling pathway, though not fully understood, is implicated in liver injury and may be a potential therapeutic target.<h4>Methods</h4>Clinical HCC, HBV, HCV and NASH samples and additional in vitro and in vivo performances were subjected to confirm the role of NOTCH1 and its downstream targets via a series of biochemical assays, molecular analysis approaches and targeted signaling pathway assay, etc. RESULTS: The present study first verified the abnormal elevation of NOTCH1 in hepatocytes from patients with steatohepatitis, HCC, HBV, HCV, and mouse models. Here, NOTCH1 is linked to hepatocellular carcinoma.