Oxyphenbutazone suppresses non-canonical inflammasome activation and protects against LPS-induced sepsis.

Sepsis remains a leading cause of mortality worldwide, yet therapies targeting proximal inflammatory receptors (e.g., TLR4) or mediators have shown limited clinical success. Non-canonical inflammasome-mediated pyroptosis represents a critical downstream pathological driver and an attractive therapeutic target for Gram-negative sepsis. Although cyclooxygenase (COX)-inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to attenuate sepsis in preclinical studies, whether COX activity regulates non-canonical inflammasome activation and subsequent pyroptosis remains unclear. Here we screened COX inhibitors and discovered that oxyphenbutazone (OPB), a withdrawn non-selective NSAID, suppressed non-canonical inflammasome-mediated pyroptosis in a largely COX-1/2-independent manner. Mechanistic analysis suggested that OPB may act at or upstream of caspase-11. Similarly, OPB appeared to inhibit canonical NLRP3 inflammasome activation at or upstream of caspase-1. In a mouse model of LPS-induced septic shock, therapeutic administration of OPB significantly improved survival, ameliorated hypothermia, attenuated serum IL-1β, and reduced tissue damage. These findings suggest that OPB may function as a largely COX-1/2-independent inhibitor of non-canonical inflammasome activation with concurrent efficacy in experimental sepsis, supporting its potential repurposing for acute inflammatory conditions following further preclinical validation.