A new cancer treatment paradigm that triggers phase separation to promote ferroptosis

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A new cancer treatment paradigm that triggers phase separation to promote ferroptosis

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Nature: A new cancer treatment paradigm that triggers phase separation to promote ferroptosis . 

Ferroptosis is a non-apoptotic cell death characterized by iron-dependent lipid peroxidation [1] .

Ferroptosis is highly related to cancer and other human diseases, and has great therapeutic prospects.

It can be used in conjunction with immunotherapy, and can even kill drug-resistant and metastatic cancer cells, so it has aroused great interest [2 ] .

Previous studies by Marcus Conrad’s team at the Neuherberg Institute of Developmental Genetics in Germany found that ferroptosis suppressor protein FSP1 (Ferroptosis suppressor protein 1) supports a powerful ferroptosis protection system for cells [3,4] (see BioArt report for details: Nature Back to Back | Iron A new pathway for death regulation ; Nature | Non-canonical vitamin K cycle can effectively inhibit ferroptosis ) .

However, due to the limited medicinal development potential of the first-generation FSP1 inhibitor iFSP1 [3] , there is an urgent need for next-generation effective in vivo FSP1 inhibitors for tumor therapy.

On June 28, 2023, the Marcus Conrad research group from the Helmholtz Munich Research Center in Germany published a research paper entitled Phase separation of FSP1 promotes ferroptosis in the journal Nature .

This article was screened, identified and developed through a small molecule library.

A new generation of FSP1 inhibitor icFSP1 was developed. Unlike iFSP1, icFSP1 does not competitively inhibit FSP1 enzyme activity, but triggers subcellular relocation and phase separation of FSP1 before ferroptosis, thereby inhibiting tumor growth.

N-terminal myristoylation, amino acid residues, and disordered low-complexity regions in FSP1 are critical for icFSP1-mediated phase separation.

This unique mechanism of action of icFSP1 leads to a new paradigm of cancer therapy by promoting FSP1 phase separation and ferroptosis, providing a theoretical basis for targeting FSP1-dependent phase separation as an effective anticancer therapy.

In order to confirm that FSP1-specific inhibitors can be used as potential drugs for refractory tumors in the future, the authors carried out small molecule library screening and identified 3-phenylquinazolinones represented by the lead compound icFSP1 as potent inhibitors of FSP1. Pharmacological Inhibitors (Figure 1) .

Treatment of cells with icFSP1 caused significant lipid peroxidation and associated ferroptosis, and icFSP1-induced cell death was rescued by ferroptosis inhibitors but not by other types of cell death inhibitors, confirming its specificity.

Compared with the iFSP1 previously discovered by the author, there is no off-target effect even at high concentrations, so icFSP1 is an excellent FSP1 inhibitor.

Figure 1

What is the mechanism of action of icFSP1 as a next-generation FSP1 inhibitor that is more effective than iFSP1?

First, the expression level of hFSP1 was not affected by icFSP1, but the subcellular localization of FSP1 was changed, and the change of subcellular localization was prior to the occurrence of lipid peroxidation and ferroptosis.

Cells treated with icFSP1 showed condensates, which did not co-localize with organelles such as lysosomes, mitochondria, lysosomes, etc. These condensates were in a droplet-like state, which made people speculate that icFSP1 might induce the relative activity of FSP1.

Unlike the previously discovered inhibitor iFSP1, icFSP1 does not competitively inhibit the activity of the FSP1 enzyme, but induces the relocation and phase separation of FSP1 from the cell membrane to the cell, which is inhibited by glutathione peroxidase 4 (GPX4) . Play synergy.

Although the precise binding site of icFSP1 to wild-type hFSP1 remains to be structurally elucidated, based on mutation analysis and AlphaFold2 prediction, the S187, L217 and Q319 residues of human FSP1 are critical for icFSP1-dependent ferroptosis.

S187\L217 and Q319 may be critical for the FSP1–FSP1 interaction that triggers phase separation in cells in the presence of icFSP1. Conceptually, icFSP1 might regulate the phase transition of FSP1, altering the phase boundary, through interactions involving residues such as S187, L217, and Q319, either directly or indirectly.

In particular, myristoylation may be integral to this process, with icFSP1 acting as a ligand that preferentially binds the myristoyl form of FSP1.

In summary, icFSP1-mediated phase separation requires several molecular features of hFSP1: including N-terminal myristoylation, specific amino acid residues such as S187, L217, and Q319, and the phase-separation protein domain IDRs and their low complexity Sequence region LCR.

To evaluate whether icFSP1 is suitable for in vivo use, the authors performed metabolic stability and pharmacokinetic analysis, and icFSP1 significantly inhibited tumor growth and reduced tumor weight without affecting body weight.

Notably, hFSP1 aggregation was significantly increased with icFSP1, suggesting that the hFSP1-specific inhibitor icFSP1 may trigger phase separation of hFSP1, thereby inhibiting tumor growth in vivo.

Figure2: Phase separation of FSP1 promotes ferroptosis

In summary, this study reports a class of potent human FSP1 inhibitors: 3-phenylquinazolinones represented by icFSP1 , which exhibit a unique mechanism of action, icFSP1 does not directly inhibit the activity of FSP1 enzymes , but triggers ferroptosis through FSP1 relocation and phase separation (Fig. 2) .

In vivo experiments show that icFSP1 can significantly inhibit tumor growth in vivo, and obvious FSP1 condensates are formed in tumor tissue, and icFSP1 does not show off-target activity, and does not affect body weight even at high concentrations.

Therefore, FSP1 is very useful in tumor therapy . potential target. Triggering ferroptosis is also a promising new paradigm against cancer , which is expected to achieve eradication of tumor cells.

references

Paper link: https://doi.org/10.1038/s41586-023-06255-6

1. Dixon, SJ et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).  

2. Viswanathan, VS et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.  Nature  547, 453–457 (2017).

3. Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor.  Nature  575, 693–698 (2019).

4. Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature  https://doi.org/10.1038/s41586-022-05022-3 (2022). 

A new cancer treatment paradigm that triggers phase separation to promote ferroptosis

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