Ferroportin mediates bevacizumab resistance and ferroptosis evasion in ovarian cancer

Adaptive drug resistance remains a major barrier in cancer therapy, driving poor patient outcomes. Bevacizumab (Bev) is a mainstay of ovarian cancer (OC) treatment, yet prolonged exposure frequently leads to resistance and diminished clinical benefit. Understanding the mechanisms underlying Bev response and tumor adaptation is therefore critical for improving therapeutic strategies. To investigate these mechanisms, we established a SKOV3 Bev-resistant tumor model. RNA-seq analysis revealed that two ferroptosis-inhibitory genes, SLC40A1 (fold change 4.01) and AKR1C2 (fold change 3.81) among the top five differentially expressed genes, implicating ferroptosis regulation as a potential determinant of Bev sensitivity. Consistently, public datasets indicate that OC cells with high SLC40A1 expression are resistant to ferroptosis, whereas low SLC40A1 correlates with ferroptosis susceptibility. In vitro experiments further demonstrated that OC cell lines with elevated SLC40A1 levels exhibit reduced labile iron pools and enhanced ferroptosis resistance. Likewise, Bev-resistant OVCAR5 and OVCAR8 cell lines derived from in vivo models showed significant upregulation of ferroportin (FPN), the protein encoded by SLC40A1, compared to parental controls. Pharmacologic inhibition of FPN increased labile iron across multiple OC cell lines, and the FPN inhibitor VIT-2763 markedly sensitized Bev-resistant cells to ferroptosis (P<0.01). Proteiomic profiling revealed that Bev-sensitive tumors accumulate higher levels of polyunsaturated fatty acids and lower glutathione (P<0.05) compared with both untreated controls and resistant tumors. Collectively, these findings indicate that Bev induces ferroptosis in OC models, while tumor-associated upregulation of FPN enables escape from this lethal stress. These data highlight FPN as a promising therapeutic target to overcome Bev resistance.