GPx4 in Bacterial Infection and Polymicrobial Sepsis: Involvement of Ferroptosis and Pyroptosis

Abstract

While it is well known that bacterial infection is the predominant cause of sepsis, the molecular pathophysiology of this clinical syndrome remains ill-defined. In this Research Highlights article, we discuss the recent research findings regarding a protective role for glutathione peroxidase-4 (GPx4) in bacterial infection and polymicrobial sepsis via modulating ferroptosis and pyroptosis, two novel modes of regulated cell death. It is suggested that GPx4, being a requisite gateway to both ferroptosis and pyroptosis, may serve as a critical molecular target for developing effective drugs for controlling infection and sepsis.

Keywords: Bacterial infection; Ferroptosis; GPx4; Lipid peroxidation; Pyroptosis; Sepsis.

FIGURE 1.. GPx-catalyzed decomposition of H₂O₂ and an organic hydroperoxide (LOOH).

As illustrated, GPx isozymes, using GSH as the electron donor, catalyze the reduction of H₂O₂ and LOOH into H₂O and an alcohol (LOH), and during the reaction, GSH is oxidized to glutathione disulfide (GSSG).GSSG is reduced back to GSH via the action of glutathione reductase (GR) using NADPH as the electron donor.

FIGURE 2.. The potential role of GPx4 in protecting against sepsis.

As illustrated, bacterial (other microbial) infections cause oxidative stress and lipid peroxidation, resulting in ferroptosis and pyroptosis, which in turn contribute to bacterial infection-induced tissue damage and sepsis. By suppressing lipid peroxidation and ferroptosis/pyroptosis, GPx4 may play an important role in counteracting inflammatory tissue injury and serve as a novel target for sepsis intervention. In this context, pharmacological inducers of GPx4, such as the Nrf2-activator D3T, could be developed as promising therapeutic modalities for treating sepsis as well as other pathological conditions associated with dysregulated ferroptosis and pyroptosis.