Celastrol Suppresses Porcine Deltacoronavirus Replication by Modulating Endoplasmic Reticulum Stress-Associated Ca2+ Balance.

Porcine deltacoronavirus (PDCoV) infection causes watery diarrhea and even death in neonatal piglets, leading to substantial economic losses. Meanwhile, emerging evidence indicates the potential risk of PDCoV to threaten human health and public safety. However, the effective vaccines or medicines are deficient. In this study, we evaluated the anti-PDCoV effect of celastrol (CE), a bioactive compound extracted from Tripterygium wilfordii. The results showed that CE significantly inhibited PDCoV replication in a dose-dependent manner and targeted multiple lifecycle stages of the virus. Network pharmacology analysis suggested a potential involvement of endoplasmic reticulum (ER)-related pathways in the antiviral mechanism of CE. Further investigation demonstrated that PDCoV infection induced calcium accumulation, which was restored to the baseline by the treatment of CE. Modulation of cellular calcium using chelating or supplementation approaches also influenced PDCoV replication, indicating an association between calcium homeostasis and viral infection. In addition, PDCoV also induced ER stress and increased the calcium level associated with ER, which was attenuated by CE administration. Pharmacological inhibition of ER stress similarly reduced viral replication and altered calcium distribution. Moreover, the molecular docking analysis further suggested that CE may interact with multiple viral proteins, indicating a potential multitarget antiviral profile. Taken together, these findings demonstrate that CE inhibits PDCoV replication in LLC-PK1 cells and is correlated with the regulation of ER stress-associated calcium homeostasis, providing mechanistic insights into host-virus interactions during PDCoV infection.