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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Ethnopharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1490759

Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis

Provisionally accepted
Rui Huang Rui Huang 1Dawei Chu Dawei Chu 1Jiandang Shi Jiandang Shi 1*Ruiqing Xu Ruiqing Xu 2Kun Wang Kun Wang 1
  • 1 General Hospital of Ningxia Medical University, Yinchuan, China
  • 2 Xi'an Honghui Hospital, Xi'an, Shaanxi Province, China

The final, formatted version of the article will be published soon.

    Osteosarcomas (OS) is a prevalent primary malignant bone tumor which lacks effective therapeutic interventions. Ferroptosis is a new form of programmed cell death characterized by irondependent accumulation of lethal lipid oxidation, which provides a potential alternative intervene for the OS treatment. Shikonin is the major bioactive component extracted from the roots of lithospermum erythrorhizon which is also known as "Zicao" in traditional Chinese medicine, has been proved to have exhibits remarkable anti-tumor properties in several cancers. However, whether ferroptosis participated in the shikonin mediated anti-OS activity still remains to be clarified. Herein, we provide evidence that shikonin possesses the capability to induce the ferroptosis, and elucidate the underlying mechanisms in the treatment of OS. In the present study, it was found that shikonin significantly suppressed OS cells proliferation and blocked the cell cycle progression in vitro. Subsequent results revealed that shikonin could trigger ferroptosis in OS cells by promoting the Fe 2+ accumulation, reactive oxygen species and lipid peroxidation formation, malondialdehyde production and mitochondrial damage. Further study showed that the effects of OS cell proliferation and death caused by shikonin could be successfully reversed by ferroptosis inhibitor ferrostatin-1, indicating that ferroptosis participated in the shikonin mediated anti-OS activity. Mechanistically, shikonin physically interacted with Nrf2, a critical regulator of ferroptosis, and influenced Nrf2 stability via inducing ubiquitin degradation, which suppressed the expression of Nrf2 downstream targets xCT and GPX4, and led to stimulating ferroptosis. Collectively, our findings indicated that shikonin induced OS cells ferroptosis through Nrf2/xCT/GPX4 regulatory axis, which might shed light on exploiting shikonin as a promising candidate for the future OS therapy.

    Keywords: Shikonin, Osteosarcoma, ferroptosis, Nrf2, XCT, GPx4

    Received: 03 Sep 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Huang, Chu, Shi, Xu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jiandang Shi, General Hospital of Ningxia Medical University, Yinchuan, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.