AND-1 Enhances Erastin-Induced Ferroptosis in Ovarian Cancer Cells by Down-Regulating SLC7A11 and NRF2

Ferroptosis is a highly synchronized form of non-apoptotic intracellular iron-dependent cell death which is regulated by multiple cellular metabolic pathways. Extensive studies suggest that ferroptosis could efficiently set the therapy resistant cancer cells on the road to ruin, thus providing new opportunities for cancer therapy. And-1 is an acidic nucleoplasmic DNA binding protein which plays a vital role in DNA replication and repair. Here in this study, we report a novel function of And-1 in regulating erastin-induced ferroptosis in ovarian cancer cells. And-1 overexpression (OE) enhanced erastin-induced ferroptosis by modulating the level of ferroptosis biomarkers such as MDA, GSH, Fe²⁺ and lipid peroxidation; while knockdown (KD) of And-1 produces opposite results. Moreover And-1(OE) suppressed the expression of NRF2, SLC7A11, and FTH1 and promoted the expression of TFR1 and ATF3 while And-1 (KD) produces opposite results. Further mechanistic study revealed that And-1 inhibits the expression of SLC7A11 by increasing ATF3 expression. Moreover, using pharmacological inhibitors, we have shown that erastin induces ferroptosis through multiple mechanisms. Taken together, our data suggest that And-1 enhanced erastin-induced ferroptosis in OC cells by inhibiting system x_c ^- expression through ATF3 and suppressing NRF2 expression.