Reagents and resources used in this study.

<div><p>Inflammasome activation drives pyroptotic cell death and the release of inflammatory cytokines, and many diseases involve its overactivation. Zinc is essential for all organisms as a trace element, but its functions in innate immunity remain undefined. Here, we reported that Zn<sup>2+</sup> inhibits caspase-1 to hinder inflammasome activation. We first identified the zinc exporter solute carrier family 30 member 1 (SLC30A1) as an inflammasome regulator, using a genome-wide CRISPR-Cas9-mediated screen. <i>SLC30A1</i> deficiency suppressed multiple inflammasomes by increasing intracellular levels of Zn<sup>2+</sup>, which bound and inhibited caspase-1 at its active site residues H<sup>237</sup>, C<sup>244</sup> and C<sup>285</sup>. Mutation of these residues almost completely blocked zinc binding. Similarly, Zn<sup>2+</sup> also inhibited caspase-4/5/11-mediated noncanonical inflammasome activation. Importantly, zinc supplementation significantly relieved cecal ligation and puncture (CLP)-induced sepsis, Imiquimod (IMQ)-induced psoriasis and Alzheimer’s disease. Thus, zinc might be used to treat inflammasome-related diseases as a broad-spectrum inflammasome inhibitor.</p></div>