GPX4 was found to negatively regulate Gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis by reducing lipid peroxidation; in contrast, conditional GPX4 knockdown in myeloid cells triggers macrophage pyroptosis with caspase-1/caspase-11-GSDMD-phospholipase C gamma 1 axis. Here, GSDMD is linked to Sepsis.