2. Academic Validation
  3. Ponicidin promotes ferroptosis to enhance treatment sensitivity in Lenvatinib-resistant hepatocellular carcinoma cells through regulation of KEAP1/NRF2

Ponicidin promotes ferroptosis to enhance treatment sensitivity in Lenvatinib-resistant hepatocellular carcinoma cells through regulation of KEAP1/NRF2

  • Phytomedicine. 2025 Jul 25:143:156824. doi: 10.1016/j.phymed.2025.156824.
Lisha Zhang 1,  Hao Wang 2,  Beibei Liang 3,  Lijuan Qin 4,  Mingzhu Zhang 5,  Xingxian Lv 4,  Shi Hu 6,  Xiaoyu Fan 7,  Wei Xie 3,  Hao Yang 8,  Gang Huang 8,  Wei Jing 9,  Jian Zhao 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, PR China; Nanchang Hongdu Hospital of TCM, Nanchang, PR China.
  • 2 Department of Oncology, The Air Force Hosptital of Northern Theater PLA, Shenyang, China.
  • 3 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, PR China; School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, PR China.
  • 4 Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
  • 5 University of Shanghai for Science and Technology, Shanghai, PR China.
  • 6 Department of Biomedical Engineering, College of Basic Medical Sciences, Second Military Medical University, Shanghai, PR China.
  • 7 Department of Molecular Biology, Shanghai Center for Clinical Laboratory, Shanghai, PR China.
  • 8 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, PR China.
  • 9 Department of Surgery, Changhai Hospital, Second Military Medical University, Shanghai, PR China. Electronic address: jingwei77@smmu.edu.cn.
  • 10 Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, PR China. Electronic address: j-zhao@vip.126.com.
PMID: 40382941 DOI: 10.1016/j.phymed.2025.156824
Abstract

Objective: This study explores the therapeutic potential of Ponicidin on Lenvatinib-resistant hepatocellular carcinoma (HCC), elucidates its mechanism in reversing Lenvatinib resistance, and provides experimental evidence for its clinical application in overcoming this resistance.

Methods: Huh7 and HCC-LM3 cells were used to construct Lenvatinib-resistant cell lines, Huh7-LR and HCC-LM3-LR. Changes in the Ferroptosis pathway post-drug resistance were observed by measuring ferroptosis-related markers. The proliferation assay were assessed by CCK-8, while the migration and invasion were measured by scratch and Transwell invasion assays. In mechanistic study, chip analysis and immunoprecipitation with biotin-labeled Ponicidin, were conducted to explore how Ponicidin overcame drug resistance. Xenograft model in nude mice was established to examine Ponicidin's anti-HCC effects In vivo. Clinical specimens were used to assess the true status of patients in Lenvatinib-resistant HCC patients.

Results: Our study reveals for the first time that Ferroptosis inhibition drives Lenvatinib resistance in HCC and identifies Ponicidin as a novel KEAP1-targeting agent to reverse this process. In vitro, Ferroptosis pathway was suppressed in Lenvatinib-resistant cells. Ponicidin suppressed proliferation, clonogenicity, migration, and invasion in these cells. The combination of Ponicidin and Lenvatinib significantly inhibited proliferation and reversed drug resistance by activating the Ferroptosis pathway. Preliminary mechanistic studies showed that Ponicidin binds to KEAP1, stabilizing the KEAP1/NRF2 interaction, inhibiting the nuclear translocation and activation of NRF2, and thereby inducing Ferroptosis to overcome Lenvatinib resistance. In vivo, the combination of Ponicidin and Lenvatinib exhibited a synergistic effect, significantly delaying tumor growth. Clinically, p-NRF2 and GPX4 expression was higher in the Lenvatinib-insensitive group, suggesting that the Ferroptosis pathway was inhibited in these patients. Thus, this study demonstrated that Ponicidin promotes Ferroptosis to enhances treatment sensitivity in Lenvatinib-resistant HCC cells through KEAP1/NRF2.

Keywords

Ferroptosis; Hepatocellular carcinoma; KEAP1; Lenvatinib resistance; NRF2; Ponicidin.

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