Dihydroartemisinin alleviates diethylnitrosamine-induced hepatocarcinogenesis by targeting a novel MAZ/TRIM50 axis

Dihydroartemisinin (DHA) has demonstrated a range of anticancer effects, and the myc-associated zinc finger protein (MAZ) has been shown to influence its anti-glioma activity. However, the role and underlying mechanisms of MAZ in DHA's anti-liver cancer effects remains poorly understood. In this study, we first established a diethylnitrosamine (DEN)-induced hepatocarcinogenesis rat model and found that DHA treatment alleviated DEN-induced liver cancer by reducing hepatotoxicity and lipid peroxidation, likely through increasing autophagy proteins. Moreover, DHA treatment suppressed MAZ expression in both liver tissues of the DEN-induced rat model and liver cancer cells. We further identified that MAZ knockdown led to the upregulation of autophagy proteins, including p62 and Beclin 1, and increased autophagosome formation in liver cancer cells, as observed under a transmission electron microscope. Notably, MAZ knockdown also enhanced the transcription of TRIM50, an E3 ubiquitin ligase involved in regulating autophagy proteins, by binding to its promoter following DHA treatment, as confirmed by dual-luciferase reporter assays. Further experiments involving TRIM50 overexpression in liver cancer cells revealed that TRIM50 promoted the expression of DHA-induced autophagy proteins through the MAPK and mTOR signaling pathways. Additionally, TRIM50 was downregulated in hepatocellular carcinoma (HCC) tissues and had a relationship with the prognosis of HCC patients. Bioinformatics analyses showed a significant correlation between TRIM50 expression and immune cell infiltration in HCC. Our findings provide new insights into the molecular mechanisms by which MAZ mediates DHA anti-liver cancer through TRIM50 transcription, supporting MAZ and TRIM50 as potential therapeutic targets for liver cancer treatment.