Tiliroside induces ferroptosis and suppresses tumor growth by synergistically targeting AKR1B1 and modulating iron metabolism in ovarian cancer cells

Aims: Ovarian Cancer (OC) is a common malignant tumor with the greatest mortality rate among gynecological tumors. Tiliroside (TIL) is a glycosidic dietary flavonoid with various pharmacological activities. The purpose of this study was to investigate the exact mechanism by which TIL eliminates OC cells.

Methods/key findings: In vitro, TIL exerted anti-tumor activities by inducing cell death and inhibiting the invasion and migration of A2780 and OVCAR8 cells. Additionally, the suppressive effect of TIL on OC cells was mainly due to the induction of Ferroptosis, as demonstrated by the fact that only ferroprostatin-1 (Fer-1) significantly inhibited the anti-tumor activity of TIL, with the accumulation of ROS, MDA, and Fe²⁺ and a reduction in GPX4 expression. SwissTargetPrediction, molecular docking and CETSA assay showed that the direct interaction between AKR1B1 and TIL decreased its stability and expression. Notably, AKR1B1 overexpression significantly attenuated the effects of TIL on the proliferation, invasion, migration and Ferroptosis on OC cells, whereas the levels of Fe²⁺ remained unaffected. Interestingly, the results of the RNA Sequencing (RNA-seq) analysis suggested that the regulation of iron homeostasis by TIL might be connected to ion transport. Western blotting and immunofluorescence confirmed that TIL could modulate iron metabolism by regulating iron ion transport and ferritinophagy, ultimately resulting in Ferroptosis. In xenograft model mice, TIL treatment inhibited tumor growth without causing substantial tissue damage.

Significance: Our research revealed that TIL simultaneously targets AKR1B1 and modulates iron metabolism, thereby inducing Ferroptosis and improving anti-tumor efficacy. As a novel drug, TIL is promising for OC treatment.

AKR1B1; Ferroptosis; Iron metabolism; Ovarian cancer; Tiliroside.