Necrosulfonamide

Necrosulfonamide is a MLKL and Gasdermin D (GSDMD) inhibitor, capable of separately inhibiting necroptosis and pyroptosis of cells. Necrosulfonamide does not affect the activation of upstream signals, but specifically inhibits the downstream executor oligomerization step. Necrosulfonamide reduces the expression of the key kinases NLRP3 and caspase-1 involved in necroptosis and pyroptosis, activate the Nrf2 pathway and the downstream antioxidant enzymes, and also downregulates a variety of inflammatory factors. Necrosulfonamide plays significant roles in various diseases such as neurodegenerative diseases (such as Parkinson’s disease), tissue damage and ischemia-reperfusion injury, inflammatory bowel disease, osteoarthritis and fracture repair, and hair loss by regulating two important programmed necrosis pathways^{[1][2][3][4][5][6][7]}. In Vitro:Necrosulfonamide (0-10 μM) blocks necrosis in both human colon cancer HT-29 cells and FADD null human T cell leukemia Jurkat cells with IC₅₀s both less than 1 μM, but it has no effect on mouse cells, for that the cysteine at the 86th position in human MLK1 is replaced by tryptophan in the mouse MLKL after covalent modification^[1].
Necrosulfonamide (6 h) acts downstream of RIP3 activation, it does not inhibit the interaction or phosphorylation between RIP1 and RIP3; but enhances these processes in RIP3-HT-29 cells^[1].
Necrosulfonamide (10 μM, 45 min-25 h) inhibits the release of inflammatory factors and pyroptosis in BMDMs and NCM460 cells necroptosis and has no effect on the vitality of the two types of cells^[4].
Necrosulfonamide (0.1-100 μM) protects primary cultured astrocytes and human astrocytes against oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced cell injury, reduces the number of PI-positive cells and inhibits the levels of necroptosis-related proteins^[5].
Necrosulfonamide (0.1-1 μM, 6 h) reverses pyroptosis-induced inhibition of proliferation and differentiation of osteoblasts through the NLRP3/caspase-1/GSDMD pathway in hFOB 1.19 cells^[6].
In Vivo:Necrosulfonamide (20 mg/kg, i.p., single dose) alleviates Lipopolysaccharide (HY-D1056A1)/D-galactosamine (HY-42682)-induced acute liver failure in mice^[2].
Necrosulfonamide (1-5 mg/kg, i.p., once daily for 3 days) reduces oxidative Stress, inflammation, and dopaminergic neuronal cell death in MPTP (HY-15608)-induced Parkinson’s disease mouse model^[3].
Necrosulfonamide (20-40 mg/kg, i.p., once other daily for 5-7 days) ameliorates Inflammatory bowel disease (IBD) in mice via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis^[4].
Necrosulfonamide (40-80 nmol, intracerebroventricular administration, single dose) produces neuroprotective effects against ischemia/reperfusion (I/R)-induced acute brain injury in rats^[5].
Necrosulfonamide promotes hair growth and prevents hair follicle degeneration in androgenetic alopecia (AGA) mice through Wnt signaling^[7].