Fig. 5: The role of inflammasome signaling pathway in ferroptosis.
From: The interaction between ferroptosis and inflammatory signaling pathways
Membrane receptors sense inflammatory signals and, in turn, activate the NF-κB signaling pathway to induce NLRP3 and IL-1β transcription. NLRP3 recruits ASC and pro-caspase 1 to trigger the assembly of the NLRP3 inflammasome, which mediates the self-cleavage of pro-caspase 1. Activated caspase 1 further cleaves pro-IL-1β and pro-IL-18, which leads to the maturation of these proinflammatory cytokines. In parallel, gasdermin D is cleaved by caspase 1, and its N-terminal domain is transferred to plasma membrane, where it forms pores, mediating the release of mature IL-1β and IL-18 and causing cell lysis (pyroptosis). During this process, iron drives NLRP3 inflammasome formation via cGAS-STING pathway, whereas GPX4 blocks GSDMD cleavage to inhibit the inflammasome pathway. In addition, lipid peroxidation induced by octanal contributes to the production of the NLRP3 inflammasome, but 4-HNE binds to NLRP3 and thereby hinders its interaction with NEK7, suppressing inflammasome activation.
