Nutlin-3 promotes HBV replication by activating mTOR-mediated autophagy

Background Currently, there are approximately 240 million individuals worldwide suffering from chronic hepatitis B infection, yet a definitive cure remains elusive. In the context of pharmaceutical interventions for this patient population, the potential issue of Hepatitis B virus (HBV) reactivation must be taken into consideration. Nutlin-3 is a small molecule of imidazoline analog, which inhibits tumor growth by suppressing the interaction between human double minute 2 (HDM2) and p53. However, whether it affects HBV replication is not clear. Methods HepG2.2.15 cells were used to assess the impact of Nutlin-3 on HBV replication. The expression of Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) was detected by ELISA. The expression of pregenomic RNA (pgRNA) and core-DNA was detected by RT-qPCR. The activation of relevant signaling pathways was assessed through Western blotting and confocal microscopy detection of the expression of associated proteins. Results We found that Nutlin-3 significantly enhances the expression of HBsAg and HBeAg, and it also promotes the expression of pgRNA and Core-DNA. Nutlin-3 promotes HBV replication independent of the HDM2. Instead, it activates the autophagy pathway through p53-mediated mTOR inhibition to promote HBV replication. Conclusion When using Nutlin-3 for cancer therapy, it’s important to be aware of the potential side effect of promoting HBV replication in individuals with chronic hepatitis B infection.