Overexpression of SLC44A4 suppresses ferroptosis and reduces lipid peroxidation via noncanonical NF-κB signaling in a NIK-dependent manner

BACKGROUND: Ovarian cancer (OC) is one of the most common gynecologic malignancies worldwide and is characterized by a high recurrence rate driven by drug resistance, contributing to poor prognosis and increased mortality. Consequently, there is an urgent need to develop novel therapeutic strategies to improve patient outcomes. Although SLC44A4 is known to be highly expressed in various tumor types, its precise functional role and underlying mechanisms in OC remain largely unexplored. OBJECTIVE: This study aims to investigate the effects and underlying mechanisms of SLC44A4 overexpression on the biological behavior of OC cells. Moreover, SLC44A4 overexpression reduces lipid peroxidation, suppresses ferroptosis, and is associated with activation of noncanonical NF-κB signaling, resulting in decreased sensitivity to the ferroptosis inducer erastin. CONCLUSION: Our findings suggest that SLC44A4 overexpression reduces lipid peroxidation and suppresses ferroptosis, with these effects being linked to the activation of noncanonical NF-κB signaling. Thus, SLC44A4 may serve as a potential target for modulating ferroptosis in OC; however, further validation, including loss-of-function studies and patient-derived sample analyses, is required.