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-α) and ferroptosis (induced by glutamate, erastin or RSL3 small chemical compounds) with EC50 in the µM 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. ### Competing Interest Statement Claire Delehouze, Marie-Therese Dimanche-Boitrel, Morgane Rousselot and Stephane Bach are the founders and members of the scientific advisory board of SeaBeLife Biotech, which is developing novel therapies for treating liver and kidney acute disorders. Peter Goekjian is member of the scientific advisory board of SeaBeLife Biotech.