Fig. 5: The role of endoplasmic reticulum stress, UPR signaling, and structural dynamics in the regulation of pyroptosis ER stress regulates cell pyroptosis through multiple branches of the UPR.

Inhibition of the RNase activity of IRE1α can lead to the accumulation of dsRNA, which in turn enhances the activation of the NLRP3 inflammasome, inducing pyroptosis. The PERK branch, through the phosphorylation of eIF2α, promotes ATF4 translation and CHOP expression. CHOP then triggers pyroptosis by inhibiting Bcl-2 and activating caspase-3, which cleaves GSDME. Additionally, ER stress induced by factors such as hypoxia can upregulate PTP1B. PTP1B, by regulating RNF213 activity, promotes the degradation of CYLD/SPATA2. This activates the NF-κB pathway, upregulating the expression of NLRP3 inflammasome components, and ultimately activating the NLRP3 inflammasome to cleave GSDMD, causing pyroptosis. The structural dynamics of the ER are also crucial: the natural compound α-MG or UBR5-mediated ubiquitination and degradation of RTN4 causes the collapse of the ER’s tubular structure and promotes ER-plasma membrane fusion to form “bubble-like” structures, directly inducing pyroptosis. This process can be accompanied by the translocation of ER marker proteins like Calnexin to pyroptotic bodies, further exacerbating mitochondrial Ca²⁺ overload and ROS bursts, creating a vicious amplification loop.