Fig. 6

Schematic representation of the mechanism of pyroptosis and inflammation in DOX-induced cardiomyopathy. After Toll-like receptors (TLR) activation, it can transduce signals through myeloid differentiation factor 88 (MyD88) or Toll/IL-1 receptor domain-containing adapter-inducing interferon-β (TRIF), activate nuclear factor (NF-κB) and induce transcriptional upregulation of inflammasome regulators nucleotide-binding domain-like receptor protein 3 (NLRP3), leading to more efficient inflammasome assembly and release of damage-associated molecular pattern (DAMPs) such as IL-1β, IL-18, TNF-α and IFN-γ, mediating the inflammatory response. DOX can activate NLRP3 to assemble with ASC and pro-caspase-1, and further activating Caspase-1. Caspase-1 has both the p20 and p10 protein domains and generates activity via self-processing into Caspase-1p10 form. Activated caspase-1 cleaves gasdermin D (GSDMD) and causes GSDMD cleavage to produce N and C terminal fragments. GSDMD N terminus binds with the plasma membrane to form transmembrane pores, causing cell swelling and rupture, releasing numerous inflammatory factors into the blood system and inducing cell pyroptosis. In addition, DOX can upregulate Bnip3 to activate caspase-3 and cleave gasdermin E(GSDME) to produce the N and C terminal fragments, inducing cell pyroptosis. (By Figdraw.)