Nigratine as first-in-class dual inhibitor of necroptosis and ferroptosis regulated cell death

Nigratine (also known as 6E11), a natural flavanone derivative, was characterized as highly specific non-ATP competitive inhibitor of RIPK1 kinase, one of the key component of necroptotic cell death signaling. We show here that nigratine inhibited both necroptosis (induced by Tumor Necrosis Factor-alpha) and ferroptosis (induced by glutamate, erastin or RSL3 small chemical compounds) with EC50 in the microM range. Altogether, the data obtained showed that nigratine is the first-in-class dual inhibitor of necroptosis and ferroptosis cell death routes and opened new therapeutic avenues for treating complex necrosis-related diseases.