GSDMD inhibitor Y1 (GI-Y1) is a selective gasdermin D (GSDMD) inhibitor, binds to GSDMD with SPR KD of 7.69 uM, shows cardioprotective effects. GI-Y1 directly binds to GST-hGSDMD with a KD value of 16.61 μM in BLI assays, inhibits the membrane oligomerization of GSDMD-N via the Arg7 residue GI-Y1 significantly inhibited the cleavage of GSDMD, while GI-Y1 had no effect on the activation of Caspase-1, Caspase-11 and GSDME, indicating the selectivity of GI-Y1 toward GSDMD. GI-Y1 (20 uM) release of IL-1β and IL-18 induced by LPS combined with nigericin (Nig) in PMA-differentiated THP-1 cells. GI-Y1 (50 mg/kg/day) protects heart against myocardial I/R injury and cardiomyocyte pyroptosis. GI-Y1 alleviates hypoxia/reoxygenation (H/R)—induced cardiomyocyte pyroptosis by targeting GSDMD.
