Gasdermin E couples viral pyroptosis to lethal hepatic lipid accumulation.

Tick-borne orthonairoviruses, including the emerging wetland virus (WELV), pose a growing public health concern as cases increase, yet their pathogenesis remains unclear. Here, we show that WELV infection causes fatal liver dysfunction in patients, characterized by elevated hepatic enzymes, triacylglycerol accumulation, and hyperinflammation. WELV induces gasdermin E (GSDME)-dependent pyroptosis in hepatocytes through mitochondrial and Fas-mediated apoptotic pathways. Viral RNA activates RIG-I/CASP3-mediated GSDME cleavage, while viral nucleoprotein undergoes CASP3-dependent processing, forming a negative regulatory feedback loop. GSDME directly interacts with fatty acid synthase (FASN) and blocks K48-linked ubiquitination to inhibit FASN degradation, driving lipid metabolic reprogramming and lethal hepatic steatosis. GSDME knockout abolishes pyroptosis and metabolic dysregulation, conferring complete protection against WELV infection. Clinically approved caspase and FASN inhibitors mitigate liver pathology and improve survival in WELV-infected mice. These findings establish a pyroptosis-metabolism axis driving orthonairovirus pathogenesis, highlighting GSDME as a critical determinant of liver injury and a promising target for antiviral therapy.