2. Academic Validation
  3. Polyphyllin I exerts anti-hepatocellular carcinoma activity by targeting ZBTB16 to activate the PPARγ/RXRα signaling pathway

Polyphyllin I exerts anti-hepatocellular carcinoma activity by targeting ZBTB16 to activate the PPARγ/RXRα signaling pathway

  • Chin Med. 2024 Aug 24;19(1):113. doi: 10.1186/s13020-024-00984-0.
Lu Shan # 1 2,  Yijun Chen # 3,  Guo An # 4,  Xiaoyu Tao 1,  Chuanqi Qiao 1,  Meilin Chen 1 2 5,  Jiaqi Li 1,  Ruichao Lin 6 7,  Jiarui Wu 8,  Chongjun Zhao 9 10
Affiliations

Affiliations

  • 1 Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
  • 2 Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
  • 3 Institute of Prescriptions and Syndromes, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 5 Department of Pharmacy, Jinjiang Municipal Hospital, Quanzhou, 362200, Fujian, China.
  • 6 Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China. linrch307@sina.com.
  • 7 Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China. linrch307@sina.com.
  • 8 Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China. exogamy@163.com.
  • 9 Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China. 1014256537@qq.com.
  • 10 Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China. 1014256537@qq.com.
  • # Contributed equally.
PMID: 39182119 DOI: 10.1186/s13020-024-00984-0
Abstract

Background: Studies have reported that polyphyllin I (PPI) had effective anti-tumor activity against hepatocellular carcinoma (HCC). However, the precise molecular mechanism of this action and the direct target remain unclear. The aim of this study was to discover the molecular targets and the exact mechanism of PPI in the treatment of HCC.

Methods: Various HCC cells and Zebrafish xenotransplantation models were used to examine the efficacy of PPI against HCC. A proteome microarray, surface plasmon resonance (SPR) analysis, small molecule transfection, and molecular docking were conducted to confirm the direct binding targets of PPI. Transcriptome and Western blotting were then used to determine the exact responding mechanism. Finally, the Anticancer effect and its precise mechanism, as well as the safety of PPI, were verified using a mouse tumor xenograft study.

Results: The results demonstrated that PPI had significant Anticancer activity against HCC in both in vitro studies of two cells and the zebrafish model. Notably, PPI selectively enhanced the action of the Zinc finger and BTB domain-containing 16 (ZBTB16) protein by directly binding to it. Furthermore, specific knockdown of ZBTB16 markedly attenuated PPI-dependent inhibition of HCC cell proliferation and migration caused by overexpression of the gene. The transcriptome and Western blotting also confirmed that the interaction between ZBTB16 and PPI also activated the PPARγ/RXRα pathway. Finally, the mouse experiments confirmed the efficacy and safety of PPI to treat HCC.

Conclusions: Our results indicate that ZBTB16 is a promising drug target for HCC and that PPI as a potent ZBTB16 agonist has potential as a therapeutic agent against HCC by regulating the ZBTB16/PPARγ/RXRα signaling axis.

Keywords

Hepatocellular carcinoma; PPARγ/RXRα signaling pathway; Polyphyllin I; ZBTB16.

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