• hepatocellular carcinoma
• oxidative stress

Hepatocellular carcinoma (HCC) is the most common primary liver cancer that usually develops in cirrhotic patients, except for progressive non-alcoholic fatty liver disease (where the tumour may develop also in non-cirrhotic liver).1 HCC is currently the leading cause of mortality in cirrhotic patients, representing the fifth most common cancer and the second leading cause of cancer mortality worldwide.1 Although screening programmes can allow to identify HCC at an earlier stage in patients at risks, still a minority of patients can survive at 5 years from diagnosis, despite treatment. Current treatment options have limitations and first-line drugs approved for systemic therapy, like sorafenib and lenvatinib, can at best offer additional 3 months of survival to HCC patients, emphasising the urgent need to identify novel molecular targets to develop more effective therapies.1

Chronic liver disease progression towards HCC development as well as HCC progression are highly affected by microenvironmental cues in a very complex scenario involving inter-relationships between cells (cancer cells, tumour-associated macrophages or fibroblasts and cancer stem cells) as well as processes or events like inflammatory response, fibrogenic progression, autophagy, hypoxic conditions and oxidative stress.2 In particular, an increase in intracellular levels of reactive oxygen species (ROS) represents a common feature of cancer cells which is usually counterbalanced by an upregulation of antioxidant defenses, particularly through the relevant Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) pathway.3 In this pathway, KEAP1, a E₂-ligase which is normally negatively regulating NRF2 protein stability via ubiquitin–proteasome degradation, is inactivated under oxidative stress; this preserves NRF2 from degradation and allows its nuclear translocation and binding to antioxidant response element (ARE) sequences in the promoter of antioxidant genes, displacing BTB domain and CNC homolog 1 (BACH1, the selective …