Pyroptosis pathway

Pyroptosis is a highly inflammatory form of programmed cell death triggered by infection or danger signals, fundamentally mediated by the activation of inflammasomes (e.g., NLRP3, AIM2) and executioner proteins in the gasdermin family, most notably gasdermin D[3][5][1][6][7]. Upon inflammasome activation, inflammatory caspases (caspase-1 in the canonical pathway, caspase-4/5/11 in the non-canonical pathway) cleave gasdermin D, liberating its N-terminal pore-forming domain to disrupt the plasma membrane, causing cell swelling, lysis, and release of cytosolic content, including pro-inflammatory cytokines IL-1β and IL-18[1][3][4][6][8]. Pyroptosis plays a role in defending against pathogens, but dysregulation contributes to inflammatory diseases, cardiovascular conditions, infections, cancer, and neurodegeneration[3][5][9]. Drug discovery efforts often target molecular effectors of the pathway such as caspase-1, NLRP3, or gasdermin D, rather than the pathway as a unit[5][10]. The "Pyroptosis pathway" is not a single druggable target (e.g., receptor, enzyme, channel), so it is not a canonical molecular target but a complex pathway comprising many proteins, principally inflammasomes, caspases (1/4/5/11), and gasdermins[1][3][5][6]. Specific effectors (like gasdermin D, caspase-1, or the NLRP3 inflammasome) are valid molecular drug targets within the pathway; the pathway as a whole is not.

Other names

Pyroptotic cell death pathwayInflammasome-mediated cell deathGasdermin-mediated cell death

Inflammasome inhibitors reduce activation of inflammatory caspases and downstream pyroptotic cell death. Caspase-1 inhibitors prevent cleavage of pro-inflammatory cytokines and gasdermin D, thereby blocking cell lysis and inflammation.