Withaferin A

Withaferin A is a steroidal lactone that has been found in W. somnifera with diverse biological activities.{21343,21342} It binds to and induces aggregation of vimentin intermediate filaments in cultured endothelial cells and fibroblasts, inducing apoptosis when used at concentrations ranging from 2 to 25 ?M. It also induces formation of perinuclear aggregates in other intermediate filament networks including peripherin, neurofilament-triplet protein, and keratin as well as disrupts the organization of microtubules and actin/microfilaments.{21342} Withaferin A induces noncanonical ferroptosis via induction of lipid peroxidation through interaction with Kelch-like ECH-associated protein 1 (KEAP1) in IMR-32 neuroblastoma cells, an effect that is blocked by the ferroptosis inhibitors ciclopirox olamine and ferrostatin-1 (Item No. 17729).{35972} It also binds to and inhibits glutathione peroxidase 4 (GPX4) in IMR-32 cells. In vivo, withaferin A (4 mg/kg) reduces intratumor GPX4 expression and induces tumor regression in an IMR-32 mouse xenograft model. Withaferin A (2 mg/kg) also inhibits angiogenesis in a mouse model of injury-induced corneal neovascularization.{21343}