SK56 is a GSDMD-NT pore inhibitor. SK56 inhibits pyroptosis ( Pyroptosis ) and the release of pyroptosis-related cytokines in macrophages and human peripheral blood leukocytes. SK56 prevents extensive cell death in human alveolar organoids in an organoid-macrophage co-culture model. SK56 prevents death from infectious shock induced by LPS or cecal ligation and puncture in mice. SK56 can be used in studies related to sepsis [1].
In Vivo, SK56 (1-4 mg/kg; intravenous injection; 4, 5, and 16 h after LPS treatment) improves survival rate, alleviates organ damage and systemic inflammation, and regulates immune cell subsets in LPS-induced sepsis mouse models[1]. SK56 (1 mg/kg; i.v.; 16 h post-CLP) exerts protective effects in a mouse model of sepsis induced by cecal ligation and puncture (CLP) by improving mouse survival rate, alleviating organ damage, and reducing systemic cytokine levels[1].
In Vitro, SK56 (15 μM, 2 h) potently inhibits the release of IL-1β and IL-18, suppresses pyroptosis (IC50 = 1.38 μM) and the release of pyroptotic cell membrane fragments in LPS + nigericin-induced THP-1 cells[1]. SK56 (0.5-15 μM, 0-300 min) increases intracellular ATP levels in a concentration-dependent manner in LPS + nigericin-induced BMDMs, and inhibits pyroptosis via recruiting ESCRT (IC50 = 1.12 μM)[1]. SK56 (15 μM; 0-70 min) translocates into LPS + nigericin-induced THP-1 cells via GSDMD-NT pores, subsequently binds to mitochondria, inhibits ROS accumulation, delays lactate dehydrogenase release, and alleviates mitochondrial injury[1]. SK56 exhibits high affinity for GSDMC-NT-GFP (with a Kd of approximately 0.22 µM) and GSDMD-NT-GFP (with a Kd of approximately 0.25 µM), and blocks the pores formed by GSDMD-NT in PDA nanoparticle hydrogels[1]. SK56 (20 μM, 2 h) inhibits the phagocytosis of GSDMD-NT pores on pyroptotic cell membrane fragments by BMDCs in LPS + nigericin-induced GSDMD-casp-BFP-transfected BMDMs[1]. SK56 (20 μM, 12 h) reduces the secretion of IL-1β in activated BMDCs[1]. SK56 (15 μM, 0.5-16 h) inhibits extensive pyroptosis and protects lung tissue in a co-culture system of human alveolar organoids and THP-1 cells induced by LPS + nigericin[1].
References:
[1]. Sun J, et al. Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response. Nat Immunol. 2025;26(10):1660-1672.
In Vivo, SK56 (1-4 mg/kg; intravenous injection; 4, 5, and 16 h after LPS treatment) improves survival rate, alleviates organ damage and systemic inflammation, and regulates immune cell subsets in LPS-induced sepsis mouse models[1]. SK56 (1 mg/kg; i.v.; 16 h post-CLP) exerts protective effects in a mouse model of sepsis induced by cecal ligation and puncture (CLP) by improving mouse survival rate, alleviating organ damage, and reducing systemic cytokine levels[1].
In Vitro, SK56 (15 μM, 2 h) potently inhibits the release of IL-1β and IL-18, suppresses pyroptosis (IC50 = 1.38 μM) and the release of pyroptotic cell membrane fragments in LPS + nigericin-induced THP-1 cells[1]. SK56 (0.5-15 μM, 0-300 min) increases intracellular ATP levels in a concentration-dependent manner in LPS + nigericin-induced BMDMs, and inhibits pyroptosis via recruiting ESCRT (IC50 = 1.12 μM)[1]. SK56 (15 μM; 0-70 min) translocates into LPS + nigericin-induced THP-1 cells via GSDMD-NT pores, subsequently binds to mitochondria, inhibits ROS accumulation, delays lactate dehydrogenase release, and alleviates mitochondrial injury[1]. SK56 exhibits high affinity for GSDMC-NT-GFP (with a Kd of approximately 0.22 µM) and GSDMD-NT-GFP (with a Kd of approximately 0.25 µM), and blocks the pores formed by GSDMD-NT in PDA nanoparticle hydrogels[1]. SK56 (20 μM, 2 h) inhibits the phagocytosis of GSDMD-NT pores on pyroptotic cell membrane fragments by BMDCs in LPS + nigericin-induced GSDMD-casp-BFP-transfected BMDMs[1]. SK56 (20 μM, 12 h) reduces the secretion of IL-1β in activated BMDCs[1]. SK56 (15 μM, 0.5-16 h) inhibits extensive pyroptosis and protects lung tissue in a co-culture system of human alveolar organoids and THP-1 cells induced by LPS + nigericin[1].
References:
[1]. Sun J, et al. Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response. Nat Immunol. 2025;26(10):1660-1672.