icFSP1 Is an in vivo Applicable FSP1 Inhibitor
Resistance 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 FSP1
By 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 Separation
Ferroptosis 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.
Reference: Nakamura T, Hipp C, Santos Dias Mourão A, et al. Phase separation of FSP1 promotes ferroptosis. Nature. 2023:1-7. doi: 10.1038/s41586-023-06255-6
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