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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1509482

Ailanthone Blocks Mitophagy to Promote mtDNA Leakage through BAX-BAK1 Pores and Suppress Hepatocellular Carcinoma Cell Proliferation

Provisionally accepted
Yan Qin Yan Qin *Ying Gao Ying Gao *Dan Wu Dan Wu *Qing-qing Liu Qing-qing Liu *Chang Su Chang Su Guan Liu Guan Liu *Le Yang Le Yang *Ming-gao Zhao Ming-gao Zhao *Jing-yue Yao Jing-yue Yao *
  • Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China

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

    Hepatocellular carcinoma (HCC), the third leading cancer mortality worldwide, shows rising incidence. The mitochondria in HCC cells are prone to damage from metabolic stress and oxidative stress, necessitating heightened mitophagy for mitochondrial homeostasis and cell survival. Thus, mitophagy inhibition is a promising HCC therapy. The traditional Chinese medicinal herb ailanthone have proved promote mitochondrial dysfunction and inhibits HCC. However, the underlying mechanism remains unclear. In this study, we demonstrated the potent anti-HCC properties of ailanthone and revealed its molecular mechanism. In vitro studies demonstrated that ailanthone effectively inhibited PINK1-PRKN-mediated mitophagy and promoted BAX-BAK1 mitochondrial pores formation through PRKN inhibition. This process led to the mitochondrial DNA (mtDNA) leakage into the cytoplasm, which subsequently triggered the induction of inflammatory factors. The inhibition of mitophagy and the activation of inflammatory response ultimately led to HCC proliferation inhibition. In vivo studies demonstrated that ailanthone exhibited stronger anti-HCC activity than 5-Fluorouracil (5-FU), with no significant adverse effects on animal body weight or the physiological functions of vital organs. In conclusion, this study highlighted the efficacy of ailanthone against HCC and elucidated its underlying molecular mechanisms, suggesting the promising therapeutic potential of ailanthone for HCC.

    Keywords: Hepatocellular Carcinoma, Ailanthone, PINK1-PRKN, mtDNA, BAX-BAK1, Inflammation

    Received: 11 Oct 2024; Accepted: 25 Nov 2024.

    Copyright: © 2024 Qin, Gao, Wu, Liu, Su, Liu, Yang, Zhao and Yao. 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:
    Yan Qin, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Ying Gao, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Dan Wu, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Qing-qing Liu, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Guan Liu, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Le Yang, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Ming-gao Zhao, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
    Jing-yue Yao, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China

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