Curcumin induces Ferroptosis in Hepatocellular Carcinoma by Regulating the P62-KEAP1-NRF2 signaling pathway

Abstract Context: Hepatocellular carcinoma (HCC) urgently requires new treatment strategies due to chemotherapy resistance and toxic side effects. Curcumin exhibits broad-spectrum anticancer activity against HCC and other malignant tumors. Ferroptosis, a form of cell death characterized by iron deposition, glutathione depletion, and lipid peroxidation, has emerged as a promising therapeutic target for cancer. The P62-KEAP1-NRF2 pathway is a key signaling pathway in ferroptosis. Objective: This study explored the mechanism by which curcumin induces ferroptosis in HCC cells by modulating the P62-KEAP1-NRF2 signaling pathway. Materials and methods: We constructed a Hepa1-6 xenograft mouse model to investigate changes in tumor growth, ferroptosis indicators, and the expression of P62, KEAP1, and NRF2. In vitro, HepG2 cell were treated with a ferroptosis inhibitor (Fer-1) or subjected to P62 overexpression, after which cell viability and key ferroptosis parameters Results: Curcumin (100 mg/kg, 15 days) significantly inhibited tumor growth, reduced glutathione (GSH) levels in tumor tissues, and increased reactive oxygen species (ROS), malondialdehyde (MDA), and Fe²⁺ content. Additionally, in vitro experiments showed that curcumin inhibited HepG2 cell growth and proliferation, induced ferroptosis in HepG2 cells, decreased P62 and NRF2 levels, and increased KEAP1 levels. These effects were inhibited by the Fer-1. Overexpression of P62 reduced the impact of curcumin on the P62-KEAP1-NRF2 pathway and ferroptosis. Discussion and conclusion: Curcumin exerts its antitumor effects by inducing ferroptosis through the inhibition of the P62-KEAP1-NRF2 signaling pathway. This study provides important scientific basis for the application of curcumin and new potential targets for studying the pathological mechanisms of hepatocellular carcinoma.