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Reactive oxygen species (ROS) regulate the activities of inflammasomes, which are innate immune signaling organelles that induce pyroptosis. The mechanisms by which ROS control inflammasome activities are unclear and may be multifaceted. Herein, we report that the protein gasdermin D (GSDMD), which forms membrane pores upon cleavage by inflammasome-associated caspases, is a direct target of ROS. Exogenous and endogenous sources of ROS, and ROS-inducing stimuli that prime cells for pyroptosis induction, promote oligomerization of cleaved GSDMD, leading to membrane rupture and cell death. We find that ROS enhance GSDMD activities through oxidative modification of cysteine 192 (C192). Within macrophages, GSDMD mutants lacking C192 show impaired ability to form membrane pores and induce pyroptosis. Reciprocal mutagenesis studies reveal that C192 is the only cysteine within GSDMD that mediates ROS responsiveness. Cellular redox state is therefore a key determinant of GSDMD activities., Competing Interests: Declaration of interests J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, and Neumora Therapeutics. E.T.C. is co-founder, equity holder, and board member of Matchpoint Therapeutics and co-founder and equity holder in Aevum Therapeutics. None of these relationships influenced this study., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)