Targeting ZBP1 to Mitigate LSDV-Driven PANoptosis in Host Cells

Lumpy skin disease virus (LSDV), first detected in China in 2019, is responsible for an immunosuppressive disease characterized by widespread cutaneous and mucosal nodules, as well as infertility in affected cattle. As an enveloped, double-stranded DNA virus with an unusually large genome, LSDV poses significant challenges for vaccine development. Z-DNA binding protein 1 (ZBP1) acts as an innate intracellular nucleic acid sensor that, upon recognizing exogenous viral nucleic acids, orchestrates multiple programmed cell death pathways. In this study, we isolated LSDV from skin vesicles collected from an infected farm in Jilin Province, China, and subsequently used it to infect MDBK bovine kidney cells. The infection induced robust upregulation of host ZBP1 expression and the activation of PANoptosis, a coordinated cell death program that integrates apoptosis, pyroptosis, and necroptosis. CRISPR/Cas9-mediated knockdown of ZBP1 significantly reduced viral titers and downregulated the expression of molecular markers associated with all three death modalities, demonstrating that LSDV-induced PANoptosis is mediated primarily through ZBP1. Furthermore, pharmacological and genetic inhibition of ZBP1 ameliorated LSDV-mediated cytopathic effects in MDBK cells. These findings delineate a ZBP1-dependent mechanism of LSDV pathogenesis and suggest that targeting ZBP1 may provide a novel therapeutic strategy against lumpy skin disease.