Ferroptosis inhibitory constituents from the fruits of Cullen corylifolium

In current study, we studied the phytochemicals of Cullen corylifolium (fruits) in which we identify twenty compounds, including two coumarins (1 and 2), three coumestans (3-5), fourchalcone (6-9), three dihydroflavones (10-12), four isoflavones (13-16), one flavonoid (17) and three meroterpenes (18-20). Among these, compounds 4, 5 and 12 were isolated from C. corylifolium for the first time. The ferroptosis inhibitory effects of the isolated phytochemicals were assessed using erastin-exposed HT22 mouse hippocampal cells. Compounds 3 and 18 showed the most potent inhibition with the IC₅₀ values of 5.21 μM and 5.41 μM, respectively. Moreover, molecular docking study showed that compound 3 possessed tremendous inhibitory affinity for human 5-lipoxygenase (5-LOX) and Kelch-like ECH-related protein 1: nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) protein-protein interactions, two important ferroptosis-related targets. These findings indicate that compound 3 (psoralidin) may be a potential therapeutic agent for the treatment of ferroptosis-related diseases.