Oxidative photocatalysis on membranes triggers non-canonical pyroptosis

Abstract Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-targeted oxidative stress remains elusive. Herein, we developed an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generated hydroxyl radicals and hydrogen peroxides via water oxidation, which was accelerated under hypoxia. Single-molecule magnetic tweezers revealed that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification revealed that oxidative damage occurred primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activated non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.