Abstract

Lumpy skin disease virus (LSDV) is a critical transboundary pathogen that causes devastating infections in cattle, buffalo, and other ruminants. The virus induces characteristic clinical manifestations, including cutaneous nodules, marked reduction in milk yield, and impaired production performance, leading to severe economic losses in the global livestock sector. Although LSDV exhibits remarkable multi-tissue tropism and persistent viral shedding in various organs, posing significant challenges for disease control, the molecular mechanisms underlying its tissue-specific adaptation remain poorly understood. Here, we established both bovine cell models and golden hamster models to elucidate the tissue-specific pathogenic mechanisms of LSDV, and further validated these findings in bovine kidney and mammary tissue samples to demonstrate their relevance in natural hosts. Our findings revealed that LSDV employs distinct cell death pathways in different tissues to facilitate host adaptation. In kidney tissue, the viral envelope protein ORF117 specifically interacts with host GAPDH, triggering its nuclear translocation and subsequent activation of the GAPDH-Siah1/p53 signaling cascade, culminating in Caspase-3-mediated apoptosis. Conversely, in mammary tissue, LSDV induces Caspase-8-dependent cleavage of Gasdermin C, promoting pyroptosis in mammary epithelial cells and substantial release of inflammatory cytokines IL-1β and IL-18. This study provides the first mechanistic insight into the molecular basis of LSDV’s tissue-specific activation of distinct cell death pathways, establishing a theoretical framework for developing targeted therapeutic interventions against lumpy skin disease. Lumpy skin disease virus (LSDV), a significant pathogen of cattle, causes severe economic losses in livestock industries worldwide. Although LSDV exhibits broad tissue tropism, the molecular mechanisms underlying its tissue-specific adaptation remain elusive. Our study revealed that LSDV