Cidofovir inhibits lumpy skin disease virus replication by targeting viral DNA polymerase and modulating host apoptosis.

Lumpy skin disease virus (LSDV) infection poses a significant threat to the global cattle industry; however, effective therapeutic options remain limited. Cidofovir, a nucleotide analog that inhibits viral DNA polymerase, presents a promising antiviral strategy. This study aimed to elucidate the mechanistic basis of Cidofovir-mediated inhibition of LSDV. The results demonstrated that Cidofovir suppressed LSDV replication and reduced viral DNA polymerase expression in a dose-dependent manner. Transcriptome sequencing (RNA-seq) analysis revealed significant enrichment of apoptotic pathways following Cidofovir treatment, and inhibitors of these pathways could reverse its antiviral effect. Further flow cytometry analysis indicated that Cidofovir exerted a dose-dependent bidirectional effect on regulating cell apoptosis: at low doses, it may indirectly reduce infection-induced apoptosis by inhibiting viral replication and DNA polymerase activity, while at high doses, the drug itself directly induced a pro-apoptotic effect, leading to a significant increase in the apoptotic rate. In conclusion, the anti-LSDV activity of Cidofovir arises not only from its direct inhibition of viral DNA polymerase but also from the clearance of viral infection through dose-dependent bidirectional regulation of apoptotic pathways. These findings provide novel theoretical insights into its antiviral mechanism and clinical application.