Upon necroptosis induction, receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) hetero-oligomerize into amyloid-like fibers which recruit mixed lineage kinase-like protein MLKL to form the necrosome. After being phosphorylated by RIPK3, MLKL undergoes conformational changes and forms disulfide bond-dependent tetramers. MLKL tetramers subsequently translocate to membrane fractions and further polymerize to form another amyloid-like fibers, which lead to plasma membrane rupture. Importantly, disulfide bond formation of MLKL is tightly controlled by the cytosolic oxidoreductase thioredoxin 1 (Trx1). Inhibition of Trx1 with compound PX-12 in some cells leads to spontaneous activation of MLKL polymerization and subsequent necroptosis. Compound necrosulfonamide (NSA) specifically conjugates cysteine 86 of human MLKL and cysteine 32 of Trx1 to block MLKL polymerization and necroptosis. There are many unanswered questions. For example, consensus has not been reached if MLKL polymers directly disrupt membrane integrity or they need to recruit other proteins such as channels to do it. And it is not clear if organelle membranes and the plasma membrane are equally susceptible to the disruption. We are actively pursuing these questions.