Ferroptosis inhibitory constituents from the fruits of <i>Cullen corylifolium</i>

Abstract

In current study, we studied the phytochemicals of <i>Cullen corylifolium</i> (fruits) in which we identify twenty compounds, including two coumarins (<b>1</b> and <b>2</b>), three coumestans (<b>3</b>-<b>5</b>), fourchalcone (<b>6</b>-<b>9</b>), three dihydroflavones (<b>10</b>-<b>12</b>), four isoflavones (<b>13</b>-<b>16</b>), one flavonoid (<b>17</b>) and three meroterpenes (<b>18</b>-<b>20</b>). Among these, compounds <b>4</b>, <b>5</b> and <b>12</b> were isolated from <i>C. corylifolium</i> for the first time. The ferroptosis inhibitory effects of the isolated phytochemicals were assessed using erastin-exposed HT22 mouse hippocampal cells. Compounds <b>3</b> and <b>18</b> 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 <b>3</b> 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 <b>3</b> (psoralidin) may be a potential therapeutic agent for the treatment of ferroptosis-related diseases.