Surface Plasmon Resonance Guided Identification of Quinolone Alkaloids from the Fruits of Tetradium ruticarpum as FSP1 Inhibitors

Ferroptosis suppressor protein 1 (FSP1), a key regulator of ferroptosis that functions independently of glutathione, has become a vital therapeutic target in ferroptosis research. However, the discovery of FSP1 inhibitors remains a significant challenge, particularly given the absence of natural FSP1 inhibitors. In this study, surface plasmon resonance (SPR)-guided fractionation of the fruit extract of Tetradium ruticarpum (FTR) led to the isolation of 12 quinolone alkaloids, including ten known compounds (1–10) and two new ones (11 and 12). Compounds 1–9 all inhibited FSP1, among which 2–4 were the most potent (IC₅₀ = 0.47 ± 0.12, 0.29 ± 0.17, and 0.52 ± 0.98 μM, respectively), exceeding the positive control icFSP by more than 50-fold. This study represents the first identification of natural FSP1 inhibitors. Our findings highlight the potential of quinolone alkaloids as novel agents targeting FSP1 and underscore the importance of exploring natural products for the development of new ferroptosis modulators.