Caspase-1 Inhibitors Show Broad Efficacy in Multisystem Inflammatory Diseases

Caspase-1 is a crucial enzyme involved in the activation of pro-inflammatory cytokines like IL-1β and IL-18, driving inflammation and pyroptosis (a highly inflammatory form of programmed cell death). Dysregulated caspase-1 activity contributes to the pathogenesis of numerous conditions, including inflammatory bowel disease (IBD) and non-alcoholic steatohepatitis (NASH). Despite their therapeutic potential, there remains a need for a comprehensive understanding of the comparative pharmacological profiles of different caspase-1 inhibitors across various inflammatory disease models.

All three caspase-1 inhibitors demonstrated significant anti-inflammatory effects across both disease models, but with varying potencies. In the IBD model, Ac-YVAD-CMK significantly reduced the disease activity index by 65% (p<0.001) and colon histological scores by 58% compared to vehicle-treated controls. Z-YVAD-FMK showed a 48% reduction in DAI, while Ac-YVAD-CHO achieved a 52% reduction. In the NASH model, Ac-YVAD-CMK was particularly effective, reducing hepatic steatosis scores by 3.5-fold and liver fibrosis by 2.8-fold (p<0.01). Ac-YVAD-CMK consistently exhibited superior efficacy in mitigating disease progression and reducing inflammatory markers across both IBD and NASH models, including a 58% decrease in plasma IL-1β levels (p<0.001). All inhibitors significantly suppressed tissue caspase-1 activity by 60-70% and reduced pro-inflammatory cytokine levels (IL-1β, IL-18) in a dose-dependent manner, with no significant adverse effects observed on body weight or liver/kidney function markers.