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

contextHepatocellular 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.

objectiveTo assess whether curcumin induces ferroptosis in HCC cells through modulation of the P62-KEAP1-NRF2-signaling pathway. MATERIALS AND

methodsA 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.

resultsCurcumin 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 DISCUSSION AND

conclusionOur 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.