Abstract IF1 is the natural inhibitor of the mitochondrial ATP synthase during hydrolytic activity. It has been found to be overexpressed in many tumors, where it acts as a pro-oncogenic protein. During oxidative phosphorylation, IF1 binds to a novel site on the OSCP subunit of ATP synthase and promotes tumorigenesis by protecting cancer cells from permeability transition pore (PTP)-dependent apoptosis. In this work, honokiol, a biphenolic compound, showed binding affinity for two sites on the OSCP subunit, as predicted by molecular docking analysis. It was shown to be effective in disrupting the IF1-OSCP interaction and sensitizing cancer cells to apoptosis. In vivo, xenografts of zebrafish injected with IF1-expressing HeLa cells showed tumor development. The same xenografts, treated with honokiol, showed a significant reduction in tumor mass, similar to untreated fish injected with IF1 KO HeLa cells. In vitro, honokiol inhibits colony formation in soft agar of IF1-expressing HeLa cells by promoting the PTP opening and cell death, without any effect on cell proliferation. Interestingly, honokiol was shown to block metastasis in fish xenografts and migration in a wound healing assay, by promoting mitochondrial swelling in both control and IF1 KO cell lines, when cells are moving to close the scratch area. In conclusion, honokiol appears to be a promising anti-cancer compound, with pro-apoptotic properties through the displacement of IF1 from the OSCP subunit of ATP synthase, and anti-metastatic effects that are due to mitochondrial PTP opening.
Grandi et al. (2026) studied this question.