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Context <p> 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.</p> Objective <p>To assess whether curcumin induces ferroptosis in HCC cells through modulation of the P62-KEAP1-NRF2-signaling pathway.</p> Materials and methods <p> 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. Complementary<i>in</i><i> vitro</i> 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.</p> Results <p>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<sup>2+</sup>.<i>In</i><i> vitro</i>, 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.</p> Discussion and conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月29日

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  • Jinlan Deng,
  • Zhijuan Wu,
  • Shangkun Ning,
  • Xu Chang,
  • Jibing Liu,
  • Yangli Yu,
  • Min Zhang,
  • Lin Zhang

摘要

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 Fe2+.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.