MLKL Activators

MLKL, or mixed lineage kinase domain-like protein, is a crucial component in the necroptosis pathway. Activation of MLKL results in a cellular death process distinct from classical apoptosis. The chemicals that activate MLKL function either by directly impacting its phosphorylation status or by indirectly modulating upstream regulators in the necroptosis pathway. GSK'872 activates RIPK3, leading to subsequent phosphorylation of MLKL. Inhibition of the apoptosis pathway, as done by Z-VAD-FMK, can shift the cell towards necroptosis, therefore promoting MLKL activation.

Interestingly, Necrostatin-1, while an inhibitor of RIPK1, can sometimes push cells toward necroptosis and MLKL activation when certain apoptotic checkpoints are compromised. Smac mimetics like BV6, LCL161, and Birinapant operate by antagonizing IAPs (Inhibitors of Apoptosis Proteins), which in turn facilitates the formation of the necrosome, a complex necessary for MLKL activation. Furthermore, certain agents induce necroptosis in response to cellular stresses or altered physiological conditions. For instance, Cycloheximide and Sorafenib can all lead to MLKL activation depending on the cellular context. Likewise, Thapsigargin and Tunicamycin induce endoplasmic reticulum stress, which can culminate in necroptosis and subsequent MLKL activation.