Sanguinarine inhibits bovine parainfluenza virus type 3 replication through CD97 suppression

Bovine parainfluenza virus type 3 (BPIV3) is a major pathogen responsible for bovine respiratory disease syndrome, posing a significant threat to cattle health. Currently, there are no effective antiviral drugs targeting BPIV3 infection. Our previous research identified Cluster of Differentiation 97 (CD97) as a positive regulator of RNA virus replication, and that sanguinarine can inhibit CD97 expression. However, the role of sanguinarine in BPIV3 infection and its underlying mechanisms remained unclear. In this study, we demonstrated that sanguinarine suppresses BPIV3 replication in a dose- and time-dependent manner. This inhibitory effect was significantly attenuated upon CD97 knockout. Furthermore, sanguinarine did not affect the CD97 mRNA level. Additionally, after treatment with the inhibitors Bafilomycin A1 and Z-VAD-FMK, sanguinarine no longer inhibited CD97 protein expression. Mechanistically, sanguinarine promotes CD97 degradation through both the autophagy receptor NBR1 and the apoptotic caspases-3/8, while also enhancing autophagy and apoptosis. Together, these findings reveal the antiviral potential of sanguinarine against BPIV3 and suggest its promise as a candidate therapeutic agent.