Targeting ferroptosis has emerged as a therapeutic vulnerability in combating therapy-resistant and dedifferentiating cancers. Therefore, new in vivo active ferroptosis-inducing compounds are urgently needed. Here we introduce a novel compound class of ferroptosis inducing agents, called icFSP1, which targets ferroptosis suppressor protein-1 (FSP1), one of the guardians of ferroptosis. Unlike our first reported FSP1-specific inhibitor iFSP1 (Doll et al., Nature 2019), icFSP does not inhibit FSP1 directly, but causes membrane detachment and phase separation of FSP1. Phase separation is a physicochemical process that is involved in numerous cellular processes including cell signaling and transcriptional regulation and is known to play a role in neurodegenerative disease and cancer. We further demonstrate that icFSP1 impairs tumor growth in vivo by inducing phase separation of FSP1. Our study thus provides the basis for targeting FSP1 as a future approach to treat certain cancers by triggering ferroptosis.

Original publication:

Phase separation of FSP1 promotes ferroptosis.

see also:

New Approach in Cancer Therapy With Innovative Mechanism-of-Action for Ferroptosis Induction