Punicic Acid in Ovarian Cancer: Anticancer Activity and Mechanistic Insights

Ovarian cancer (OC) remains the deadliest gynecological malignancy, with aged tumor microenvironments linked to poorer outcomes. Our prior work identified reduced levels of free fatty acids (FFAs) within tumor-surrounding adipose tissue of aged OC xenograft rats compared to younger counterparts. In this study, we investigated the therapeutic potential of one such FFA, punicic acid (PunA). We evaluated PunA's effects on OC and normal cell viability and compared its activity with that of its structural isomer, α-eleostearic acid (α-ESA). Both compounds decreased OC cell viability; however, α-ESA was cytotoxic to normal cells, whereas PunA selectively impaired OC cell viability while sparing normal cells. Additionally, PunA enhanced cisplatin efficacy, demonstrating its potential for use in combination therapy to reduce cisplatin dosage and toxicity without compromising antitumor activity. Mechanistically, PunA induced ferroptosis in OC cells while sparing normal cells by differently modulating lipid peroxidation, fatty acid oxidation, and mitochondrial function. Transcriptomic profiling further revealed coordinated gene expression changes associated with oxidative stress and ferroptosis in PunA-treated OC and normal cells. In a preliminary C57BL/6J-ID8 OC mouse model, PunA suppressed tumor growth. Collectively, these findings identify PunA as a promising therapeutic candidate for OC, acting through ferroptosis and mitochondrial dysfunction, and enhancing cisplatin efficacy while sparing normal cells.