Curcumin induces ferroptosis in hepatocellular carcinoma by regulating the P62-KEAP1-NRF2-signaling pathway.

CONTEXT: Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited treatment options owing to chemotherapy resistance and severe systemic toxicity. Curcumin demonstrates broad-spectrum antitumor activity against HCC and various other malignancies. Ferroptosis, a regulated form of cell death driven by iron overload, glutathione depletion, and lipid peroxidation, has recently gained attention as a potential therapeutic strategy in cancer treatment. Among the regulatory networks of ferroptosis, the P62-KEAP1-NRF2-signaling pathway plays a pivotal role. OBJECTIVE: To assess whether curcumin induces ferroptosis in HCC cells through modulation of the P62-KEAP1-NRF2-signaling pathway. MATERIALS AND METHODS: A Hepa1-6 xenograft mouse model was developed to examine curcumin-mediated effects on tumor growth, ferroptosis markers, and the expression profiles of P62, KEAP1, and NRF2. Complementaryin vitro experiments were performed using HepG2 cells treated with a ferroptosis inhibitor (ferrostatin-1) or subjected to P62 overexpression, followed by assessment of cell viability and ferroptosis-associated parameters. RESULTS: Curcumin administration (100 mg/kg for 15 days) markedly suppressed tumor growth, reduced glutathione levels in tumor tissues, and enhanced the accumulation of reactive oxygen species, malondialdehyde, and Fe(2+).In vitro, curcumin inhibited HepG2 cell proliferation, promoted ferroptotic cell death, downregulated P62 and NRF2 expression, and upregulated KEAP1 expression. These effects were reversed by ferrostatin-1 treatment. Moreover, P62 overexpression significantly attenuated the ability of curcumin to regulate the P62-KEAP1-NRF2-signaling pathway and induce ferroptosis. DISCUSSION AND CONCLUSION: Our findings demonstrate that curcumin suppresses the P62-KEAP1-NRF2-signaling pathway to induce ferroptosis, a key mechanism underlying its anti-tumor effects. This study not only provides a novel scientific basis for the application of curcumin but also reveals potential therapeutic targets for hepatocellular carcinoma.