Marine Natural Product Chagosendine C Induces Cuproptosis in Colorectal Cancer Cells by Targeting FDX1

Colorectal cancer (CRC) treatment is hampered by high recurrence rates and drug resistance. Cuproptosis, a copper-induced cell death mechanism, offers a new therapeutic approach. Here, we identified a marine natural product, chagosendine C (CHC), which kills tumor cells by increasing the intracellular copper ion concentration. CHC and related metal coordination homodimer alkaloids were rapidly synthesized and purified for further pharmacological study. In vitro, CHC significantly inhibited HCT116 and RKO CRC cell growth, induced G1 phase arrest and cell death, and overcame oxaliplatin resistance. In vivo, CHC suppressed colorectal tumor growth in mice at 40 mg/kg without obvious toxic effects. Mechanistically, CHC induces cuproptosis by targeting FDX1, increasing intracellular copper ions and ROS levels in tumor cells, and leading to cell death. Thus, CHC presents a novel CRC treatment strategy, showing strong antitumor activity and potential to overcome oxaliplatin resistance with promising clinical prospects.