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Sorafenib sensitization in tumor therapy by iron overload and AMPK activation

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Abstract

Sorafenib, as a first-line drug for advanced hepatocellular carcinoma (HCC), could trigger ferroptosis by inhibiting cystine/glutamate transporter. However, low-level intracellular iron and insufficient activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) confer impaired response to sorafenib. In this study, a unique sorafenib nanocomposite dexterously modified with Fe-Material of Institut Lavoisier (sora@Fe-MIL) was synthesized to escalate intracellular iron level and activate AMPK, further potentiating the ferroptotic effect of sorafenib. Remarkably, this strategic deployment of sora@Fe-MIL triggered an extensive demise of cancer cells, while manifesting negligible deleterious impact on normal cells. Two prominent ferroptosis biomarkers, glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), underwent pronounced downregulation, underscoring the efficacy of this strategy in inducing ferroptosis. Furthermore, the bioactivity of AMPK was considerably elevated, and its downstream targets were conspicuously inhibited by the treatment with sora@Fe-MIL. Using orthotopic HCC animal models, we observed a substantial suppression of primary in situ tumor growth, and ribonucleic acid (RNA) sequencing elucidated an elevated degree of ferroptosis and AMPK activation with the treatment of sora@Fe-MIL. In conclusion, we proposed that the meticulously designed strategy for secure and efficacious iron release and AMPK activation could significantly potentiate the ferroptotic impact of sorafenib, thus resuscitating its therapeutic response in HCC patients.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 82173143 and 82373409). The authors also acknowledge the support from the Top Young Talents Project of the Special Support Program for High-Level Talents in Shaanxi Province (2020–2025), the Fundamental Research Funds for the Central Universities (Nos. D5000210635 and D5000210829), and General Key R&D Projects in Shaanxi Province (No. 2024SF-YBXM-439).

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Author notes

  1. Jun Zhu, Shoujie Zhao, Yejing Zhu, and Shouzheng Ma contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Jun Zhu, Yejing Zhu & Lei Liu

  2. Department of General Surgery, The Southern Theater Air Force Hospital, Guangzhou, 510602, China

    Jun Zhu

  3. Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

    Shoujie Zhao, Yejing Zhu & Bo Wang

  4. Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

    Shouzheng Ma

  5. Department of Neurology, Airborne Army Hospital, Wuhan, 430012, China

    Tenghui Han

  6. Key Laboratory of Modern Teaching Technology (Ministry of Education), Shaanxi Normal University, Xi’an, 710062, China

    Fenghua Xu

  7. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, Xi’an, 710032, China

    Huichen Li

  8. Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Northwestern Polytechnical University, Xi’an, 710072, China

    Zhixiong Guo, Da Chen, Yongquan Qu & Zhimin Tian

  9. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, 710032, China

    Junlong Zhao

  10. Department of Pediatrics, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710000, China

    Junlong Zhao

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  1. Jun Zhu
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  2. Shoujie Zhao
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  8. Bo Wang
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  10. Da Chen
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  11. Yongquan Qu
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  13. Junlong Zhao
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  14. Lei Liu
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Correspondence to Yongquan Qu, Zhimin Tian, Junlong Zhao or Lei Liu.

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Zhu, J., Zhao, S., Zhu, Y. et al. Sorafenib sensitization in tumor therapy by iron overload and AMPK activation. Nano Res. (2024). https://doi.org/10.1007/s12274-024-6602-9

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  • DOI: https://doi.org/10.1007/s12274-024-6602-9

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