Infection of macrophages by mpox virus activates inflammasome and cell death, informing multitarget therapeutic strategies.

Severe mpox virus (MPXV) infection causes immunopathological manifestations in patients. Here, we provide clinical evidence of MPXV-induced inflammation in a large patient cohort and demonstrate direct macrophage infection in skin tissues from an autopsied mpox patient. In human macrophages, MPXV efficiently enters, replicates, and produces infectious particles. Infection activates both AIM2 and NLRP3 inflammasomes, triggering inflammatory responses and three forms of programmed cell death: pyroptosis, apoptosis, and necroptosis. Inflammasome inhibition reduces MPXV-induced inflammation and cell death without affecting viral replication. Screening clinically used anti-inflammatory drugs identified flufenamic acid, which suppresses MPXV-induced inflammation and cell death and, unexpectedly, also inhibits viral infection. Combined treatment with flufenamic acid and the antiviral brincidofovir further enhances suppression of viral infection, inflammatory response, and cell death, while largely preventing MPXV-induced transcriptomic reprogramming in macrophages. These effects were consistent across clade IIb, Ia, and Ib strains associated with the 2022-2023 global and recent African outbreaks. Together, our findings provide insight into MPXV immunopathology and support multitarget therapeutic strategies for severe mpox.