Scutellarin inhibits pyroptosis via selective autophagy degradation of p30/GSDMD and suppression of ASC oligomerization

Most of the pyroptosis inhibitors targeted Gasdermin D (GSDMD) are functioning by restraining GSDMD-N (p30) oligomerization. For the first time, this work discovered a pyroptosis inhibitor taking effect by degrading p30 and GSDMD. As the principal bioactive constituent in Erigeron breviscapus , scutellarin (SCU) assumes a pivotal role in the realm of anti-inflammatory processes. In this study, SCU demonstrated efficacy in hindering pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome, absent in melanoma 2 (AIM2) inflammasome, NLR-family CARD-containing protein 4 (NLRC4) inflammasome, and that activated through the non-canonical pathway. The inhibitory effect is achieved by thwarting apoptosis-associated speck-like protein containing CARD (ASC) oligomerization and inducing the ubiquitin-dependent selective autophagy of p30/GSDMD. Throughout the autophagic process, SCU facilitates selective autophagy of the pyroptosis executor p30/GSDMD through K33-linked polyubiquitination at Lys51 catalyzed by the E3 ligase tripartite motif-containing 21 (TRIM21). This process contributes to the recognition of p30/GSDMD by the cargo receptor sequestosome 1 (SQSTM1)/p62. The characteristic positions SCU as a prospective clinical intervention for a broader spectrum of inflammatory-related disorders. • SCU inhibits pyroptosis stimulated via multiple pathways. • SCU inhibits pyroptosis through abrogating ASC oligomerization and facilitating the degradation p30/GSDMD. • SCU preferentially targets p30 for degradation over GSDMD under co-existing conditions. • SCU degrades p30/GSDMD through ubiquitin-dependent autophagic machanism. • E3 ligase TRIM21 plays an important role in the degradation induced by SCU.