Identification of Penexanthone A as a Novel Chemosensitizer to Induce Ferroptosis by Targeting Nrf2 in Human Colorectal Cancer Cells

Ferroptosis has emerged as a potential mechanism for enhancing the efficacy of chemotherapy in cancer treatment. By suppressing nuclear factor erythroid 2-related factor 2 (Nrf2), cancer cells may lose their ability to counteract the oxidative stress induced by chemotherapy, thereby becoming more susceptible to ferroptosis. In this study, we investigate the potential of penexanthone A (PXA), a xanthone dimer component derived from the endophytic fungus Diaporthe goulteri, obtained from mangrove plant Acanthus ilicifolius, to enhance the therapeutic effect of cisplatin (CDDP) on colorectal cancer (CRC) by inhibiting Nrf2. The present study reported that PXA significantly improved the ability of CDDP to inhibit the activity of and induce apoptosis in CRC cells. Moreover, PXA was found to increase the level of oxidative stress and DNA damage caused by CDDP. In addition, the overexpression of Nrf2 reversed the DNA damage and ferroptosis induced by the combination of PXA and CDDP. In vivo experiments using zebrafish xenograft models demonstrated that PXA enhanced the therapeutic effect of CDDP on CRC. These studies suggest that PXA enhanced the sensitivity of CRC to CDDP and induce ferroptosis by targeting Nrf2 inhibition, indicating that PXA might serve as a novel anticancer drug in combination chemotherapy.