MG132-mediated inhibition of rabies virus replication via the Nrf2/SQSTM1/PINK1/Parkin autophagy pathway

Rabies virus (RABV), a fatal neurotropic virus, still lacks effective antiviral drugs for treatment once symptoms appear. MG132 acts as a novel therapeutic agent against viral infection, inhibits the degradation of nuclear factor erythroid-derived 2-like 2 (Nfe2l2; Nrf2), and enhances SQSTM1 expression in mouse hypothalamic organotypic cultures. Rapamycin-induced autophagy and Parkin-mediated mitophagy could also be inhibited by MG132. Autophagy signaling was triggered by RABV replication, but the antiviral effects of MG132 against RABV remained unclear. Here, we showed that MG132 exerted potent inhibitory activity against different viral strains (CVS-11 and CTN strains), with an efficacy comparable to that of ribavirin and higher than that of T705 in vitro. We further demonstrated that MG132 inhibited RABV replication by disrupting the Nrf2/SQSTM1/PINK1/Parkin pathway, with SQSTM1 acting as a key mediator. MG132 also prevented SQSTM1 degradation and enhanced colocalization between SQSTM1 and PINK1/Parkin. In vivo, MG132 (10 mg/kg) attenuated body weight loss and prolonged survival of RABV-infected mice by 40%. Overall, our findings indicated that MG132 inhibits RABV replication via the Nrf2/SQSTM1/PINK1/Parkin-related autophagy pathway and merits further investigation as an potential anti-RABV drug.