Caspase-1 inhibition: mechanistic insights and comprehensive review of reported inhibitors to date

Caspase-1 is a key protease that regulates inflammation by mediating the maturation of pro-inflammatory cytokines IL-1β and IL-18 as well as inducing the pyroptotic cell death. Dysregulation in caspase-1 activity is implicated in various inflammatory, autoimmune and metabolic disorders. This review systematically analyzes natural, synthetic and computationally predicted caspase-1 inhibitors, emphasizing their structural, mechanistic and pharmacological characteristics. We provide data on cellular and enzymatic inhibition, including IC₅₀ values when they are available and list the compounds that have moved on to preclinical or clinical trials. Selective inhibition of caspase-1 remains challenging because the catalytic domain and substrate-binding pocket are highly conserved among caspase family, which makes it challenging to design specific inhibitors. Although, numerous candidates reported exhibit promising caspase-1 inhibitory activities, however, there is still a lack of research regarding caspase-1-specific inhibitors, and further studies are required to investigate novel and effective caspase-1 inhibitors, through in vivo, in vitro, and in silico approaches and their cytotoxicity, bioavailability and solubility.