icFSP1 Is an in vivo Applicable FSP1 InhibitorResistance to chemotherapy or metastasis is an important clinical problem in cancer. Notably, during de-differentiation or metabolic rewiring, certain malignant cancer cells acquire an intrinsic vulnerability to ferroptosis. Therefore, targeting ferroptosis has shown great promise as an approach to cancer therapy. In 2019, a team of researchers around Marcus Conrad, Director of the Institute of Metabolism and Cell Death at Helmholtz Munich, had already identified the first FSP1-specific inhibitor, known as iFSP1. "However, this compound is not suitable for in vivo use and exhibits off-target effects at high concentrations," Conrad explained. To identify in vivo active ferroptosis inducers targeting FSP1, the team performed a screening campaign in cells, followed by DMPK ("drug metabolism and pharmacokinetics") validation studies. These efforts eventually led to the identification of icFSP1 as a novel class of compounds that sensitize many human cancer cells to ferroptosis and attenuate tumor growth in vivo.
icFSP1 Triggers Phase Separation of FSP1By investigating the underlying mechanism-of-action (MoA) of icFSP1 in detail, the team further showed that icFSP1 does not inhibit FSP1 enzyme activity directly, but rather triggers the subcellular relocalization of FSP1 in a process known as phase separation. These results are in contrast to the MoA of the first FSP1 inhibitor iFSP1. Toshitaka Nakamura, lead author of the study, further explains that "icFSP1-induced FSP1 condensations require distinct structural components and N-terminal myristoylation" as demonstrated by using recombinant FSP1 proteins as well as different cell lines and tumor samples.
Breakthrough: Linking Ferroptosis and Phase SeparationFerroptosis has attracted overwhelming interest in many fields including cancer, neurodegenerative diseases, and ischemia/reperfusion injury similar to the process of phase separation, a fundamental physical phenomenon underlying signal transduction and basic biology related to multiple diseases. This study unravels for the first time a link between ferroptosis and phase separation. "Our study will therefore serve as a good model for the further development of innovative therapeutic approaches in certain diseases, including cancer, in which ferroptosis/phase separation plays an important role," explains Conrad, providing a promising outlook for the future.
Nakamura T, Hipp C, Santos Dias Mourão A, Borggräfe J, Aldrovandi M, Henkelmann B, Wanninger J, Mishima E, Lytton E, Emler D, Proneth B, Sattler M, Conrad M.
Phase separation of FSP1 promotes ferroptosis.
Nature. 2023 Jun 28. doi: 10.1038/s41586-023-06255-6