Bergamottin pretreatment attenuates cisplatin-induced acute kidney injury in mice by inhibiting BACE-1-mediated ferroptosis.

Bergamottin is a natural furanocoumarin compound that possesses antioxidative and anticancer properties. However, the effect of bergamottin (BGM) on acute kidney injury (AKI) is unknown. Human renal tubular HK-2 cells and mice that received cisplatin were pretreated with BGM, after which their cytotoxicity and renal function were evaluated. BGM pretreatment alleviated cisplatin-induced cytotoxicity in vitro. Moreover, synergistic protection against cisplatin-induced cytotoxicity was observed when BGM and apoptosis, autophagy, or necrosis inhibitors were used together. There was no synergistic effect between BGM and the ferroptosis inhibitor. Furthermore, BGM significantly inhibited ferroptosis induction-induced damage to HK-2 cells. BGM pretreatment alleviated renal dysfunction and pathological damage by reducing renal proinflammatory cytokines and inhibiting inflammatory cell infiltration, lipid peroxidation and ferroptosis. Based on predictions by SwissTarget and molecular docking, BGM strongly interacts with residues of beta-secretase 1 (BACE-1) via hydrogen and hydrophobic interactions. Moreover, BACE-1 expression was significantly upregulated in the kidneys of AKI mice and HK-2 cells treated with cisplatin but markedly reduced following BGM intervention. Interestingly, siRNA-mediated silencing of BACE-1 in vitro substantially abolished the protective effect of BGM on HK-2 cells that received cisplatin. BGM effectively alleviated AKI by targeting BACE-1 to reduce ferroptosis, suggesting that BGM could be developed as a potential agent for managing and pretreating AKI.