Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger 
pyroptosis, a lytic form of cell death that is crucial for immune defences and 
diseases. GSDMD contains a functionally important gasdermin-N domain that is 
shared in the gasdermin family. The functional mechanism of action of gasdermin 
proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin 
proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and 
cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and 
artificially transformed bacteria. Gasdermin-N moved to the plasma membrane 
during pyroptosis. Purified gasdermin-N efficiently lysed 
phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes 
made of artificial or natural phospholipid mixtures. Most gasdermin pores had an 
inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal 
structure of GSDMA3 showed an autoinhibited two-domain architecture that is 
conserved in the gasdermin family. Structure-guided mutagenesis demonstrated 
that the liposome-leakage and pore-forming activities of the gasdermin-N domain 
are required for pyroptosis. These findings reveal the mechanism for pyroptosis 
and provide insights into the roles of the gasdermin family in necrosis, 
immunity and diseases.