We recently reported on the development of a unique cancer-targeting peptide called NAF-1 (derived from CISD2/NAF-1). NAF-1 selectively permeates the plasma membrane (PM) of cancer cells, but not healthy cells, causing the activation of apoptotic and ferroptotic cell death pathways specifically in cancer cells. NAF-1 also targets and shrinks human breast and ovarian cancer tumors in a xenograft mice model system without any apparent side effects. Although the specific permeation of NAF-1 through cancer cell PMs was studied, and its cancer killing effects validated and , little is known about how NAF-1 exerts its biological activity once it enters cancer cells. Here, we report that NAF-1 targets the CISD2/NAF-1 protein of cancer cells and disrupts its homodimeric structure. We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT ) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-1 (at two different orientations) have higher anticancer activity compared to monomeric NAF-1 . Our findings shed new light on the biological activity of NAF-1 and bring it closer to becoming a potential new anticancer drug.
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| http://dx.doi.org/10.1101/2025.01.07.630758 | DOI Listing |
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