Caspase-5 (CASP5)

Caspase-5 is a cysteine protease predominantly known for mediating inflammatory programmed cell death (pyroptosis) in response to intracellular lipopolysaccharide (LPS) and Gram-negative bacterial infections. The protein is transcriptionally upregulated by inflammatory signals, such as interferon-gamma and LPS, and functions in the cytoplasm as part of the non-canonical inflammasome. Once activated, caspase-5 cleaves gasdermin D, enabling pore formation in cellular membranes that release inflammatory cytokines (such as IL-1 and IL-18), thereby amplifying the immune response. Caspase-5's action is crucial for antibacterial defense but also implicated in pathological inflammatory conditions like sepsis and IBD. While broad-spectrum caspase inhibitors have shown promise in experimental and early clinical contexts to reduce tissue injury, no drug specifically targeting caspase-5 alone has succeeded in clinical development, partly due to safety and specificity challenges. Caspase-5 is part of a small cluster of human inflammatory caspases, with mouse models relying on the ortholog caspase-11.

Other names

Caspase-5Caspase-5 subunit p20Caspase-5 subunit p10ICH3ICE(rel)IIIICEREL-IIIProtease ICH-3Protease TYapoptosis-related cysteine peptidaseapoptosis-related cysteine protease

Inhibition of caspase catalytic activity (prevents apoptosis and pyroptosis); Inhibition of gasdermin D pore formation (blocks cell lysis and inflammatory cytokine release downstream of caspase-5); Modulation of IL-1 and IL-18 signaling (by affecting caspase-mediated cytokine processing)