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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 IC\u2085\u2080 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\u20131-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.<\/jats:p>","DOI":"10.1007\/s10787-026-02361-9","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:07:20Z","timestamp":1787285240000},"page":"5953-5973","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Caspase-1 inhibition: mechanistic insights and comprehensive review of reported inhibitors to date"],"prefix":"10.1007","volume":"34","author":[{"given":"Asif","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atta","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maira Gabriela","family":"Paetzold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio Augusto Vicente","family":"Seixas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2361_CR1","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.taap.2013.03.027","volume":"270","author":"I Ahmad","year":"2013","unstructured":"Ahmad I, Muneer KM, Tamimi IA et al (2013) Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome. 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