In this paper, Gasdermin D pore structure reveals preferential release of mature interleukin-1, Ruan and collaborators reported the cryo-EM structure of human Gasdermin D (GSDMD) pore, an inflammatory cell death executioner molecule, at 3.9 Å resolution. GSDMD pore exhibits large differences in symmetry and dimensions from the previously reported GSDMA3, a mouse homolog. Beyond the structure of the human GSDMD pore, the paper also demonstrated that GSDMD forms an acidic shield that directly regulates IL-1 secretion via a charge-based mechanism. This discovery will facilitate future investigation into the GSDMD secretome and, to our knowledge, first proposes how large transmembrane pores may achieve substrate selectivity. This study is a collaborative effort between Dr. Ruan’s lab and the laboratories of Wu and Lieberman at Harvard Medical School, the laboratory of Greka at Broad Institute of MIT, and the laboratory of Jacobson at the University of California San Francisco.