Endoplasmic reticulum stress and pyroptosis signaling axis (ER stress-pyroptosis axis)

The Endoplasmic reticulum stress and pyroptosis signaling axis is a complex biochemical pathway that links cellular proteostatic imbalance to a highly inflammatory form of programmed cell death known as pyroptosis. In cancer cells, this axis is often activated by the accumulation of unfolded proteins within the ER lumen, which triggers the Unfolded Protein Response (UPR) through sensors such as Protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Inositol-requiring enzyme 1 (IRE1) (Oakes & Papa, 2015, Annual Review of Pathology). While the UPR initially serves as a pro-survival mechanism, chronic or excessive stress leads to the upregulation of C/EBP homologous protein (CHOP), which can stimulate the assembly of the NLRP3 inflammasome (Bronner et al., 2015, Nature Communications). This activation results in the recruitment of Caspase-1, which cleaves Gasdermin D (GSDMD) into its active N-terminal fragment, forming pores in the plasma membrane that cause cell lysis and the release of pro-inflammatory cytokines like IL-1β and IL-18 (Shi et al., 2015, Nature). Pharmacological modulation of this axis, such as through the use of proteasome inhibitors like Bortezomib or GSDMD inhibitors like Disulfiram, is being investigated to induce immunogenic cell death in tumors or to mitigate inflammatory damage in other diseases (Zheng et al., 2023, Frontiers in Oncology). However, the ubiquitous nature of ER stress signaling and the potential for systemic inflammation present significant challenges for therapeutic development (Galluzzi et al., 2018, Cell Death & Differentiation).

Other names

Endoplasmic reticulum stress-induced pyroptosisUPR-pyroptosis axisEndoplasmic reticulum stress-mediated inflammatory cell deathER stress-NLRP3-GSDMD pathway

Induction of chronic ER stress leads to the activation of the unfolded protein response (UPR), which triggers the assembly of the NLRP3 inflammasome and subsequent caspase-mediated cleavage of gasdermin D, resulting in lytic cell death (Zheng et al., 2023, Frontiers in Oncology).