Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
July-2025 Volume 32 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
July-2025 Volume 32 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML

  • Supplementary Files
    • Supplementary_Data.pdf
Article Open Access

Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis

  • Authors:
    • Weixia Liu
    • Guodi Wu
    • Jing Wang
    • Shanshan Wu
    • Zhi Chen
  • View Affiliations / Copyright

    Affiliations: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 202
    |
    Published online on: May 13, 2025
       https://doi.org/10.3892/mmr.2025.13567
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Glutathione peroxidase 4 (GPx4; also known as phospholipid hydroperoxide glutathione peroxidase) inhibits cell death, including apoptosis and ferroptosis, by reducing lipid peroxidation. In addition, western blot assays showed that GPx4 protein levels were elevated in hepatocellular carcinoma (HCC) cells following triptolide (TPL) treatment. Therefore, it was hypothesized that HCC cells might develop partial resistance to TPL‑induced cytotoxicity through upregulation of the GPx4 protein. To enhance anti‑proliferative efficacy, the present study co‑treated HCC cells with a combination of TPL and RAS‑selective lethal 3 (RSL3), a well‑characterized GPx4 activity inhibitor. Subsequent experimental data produced from Cell Counting Kit‑8 and flow cytometric analyses demonstrated that co‑administration of TPL and RSL3 promoted HCC cell apoptosis, elevated intracellular reactive oxygen species levels and induced ferroptosis. These collective findings suggested that co‑treatment with TPL and RSL3 may induce both apoptotic and ferroptotic pathways in HCC cells.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Ganesan P and Kulik LM: Hepatocellular carcinoma: New developments. Clin Liver Dis. 27:85–102. 2023. View Article : Google Scholar : PubMed/NCBI

2 

Alawyia B and Constantina Constantinou: Hepatocellular carcinoma: A narrative review on current knowledge and future prospects. Curr Treat Options Oncol. 24:711–724. 2023. View Article : Google Scholar : PubMed/NCBI

3 

Liu J, Shen M, Yue Z, Yang Z, Wang M, Li C, Xin C, Wang Y, Mei Q and Wang Z: Triptolide inhibits colon-rectal cancer cells proliferation by induction of G1 phase arrest through upregulation of p21. Phytomedicine. 19:756–762. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Oliveira A, Beyer G, Chugh R, Skube SJ, Majumder K, Banerjee S, Sangwan V, Li L, Dawra R, Subramanian S, et al: Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F. Lab Invest. 95:648–659. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Wei YS and Adachi I: Inhibitory effect of triptolide on colony formation of breast and stomach cancer cell lines. Zhongguo Yao Li Xue Bao. 12:406–410. 1991.PubMed/NCBI

6 

Wang H, Ma D, Wang C, Zhao S and Liu C: Triptolide inhibits invasion and tumorigenesis of hepatocellular carcinoma MHCC-97H cells through NF-κB signaling. Med Sci Monit. 22:1827–1836. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Li SG, Shi QW, Yuan LY, Qin LP, Wang Y, Miao YQ, Chen Z, Ling CQ and Qin WX: C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 37:512018. View Article : Google Scholar : PubMed/NCBI

8 

Yu L, Qian J, Xue X, Pang M, Wang X, Li X, Tian M, Lu C, Xiao C and Liu Y: Application of galactosylated albumin for targeted delivery of triptolide to suppress hepatocellular carcinoma progression through inhibiting de novo lipogenesis. Biomed Pharmacother. 179:1174322024. View Article : Google Scholar : PubMed/NCBI

9 

Alsaied OA, Sangwan V, Banerjee S, Krosch TC, Chugh R, Saluja A, Vickers SM and Jensen EH: Sorafenib and triptolide as combination therapy for hepatocellular carcinoma. Surgery. 156:270–279. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Li Z, Yang G, Han L, Wang R, Gong C and Yuan Y: Sorafenib and triptolide loaded cancer cell-platelet hybrid membrane-camouflaged liquid crystalline lipid nanoparticles for the treatment of hepatocellular carcinoma. J Nanobiotechnology. 19:3602021. View Article : Google Scholar : PubMed/NCBI

11 

Xi C, Peng S, Wu Z, Zhou Q and Zhou J: Toxicity of triptolide and the molecular mechanisms involved. Biomed Pharmacother. 90:531–541. 2017. View Article : Google Scholar : PubMed/NCBI

12 

Imai H and Nakagawa Y: Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med. 34:145–169. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Nomura K, Imai H, Koumura T, Arai M and Nakagawa Y: Mitochondrial phospholipid hydroperoxide glutathione peroxidase suppresses apoptosis mediated by a mitochondrial death pathway. J Biol Chem. 274:29294–29302. 1999. View Article : Google Scholar : PubMed/NCBI

15 

Nomura K, Imai H, Koumura T, Kobayashi T and Nakagawa Y: Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis. Biochem J. 351:183–193. 2000. View Article : Google Scholar : PubMed/NCBI

16 

Yang WS and Stockwell BR: Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 15:234–245. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Liu W, Yang Y, Wang J, Wu S and Chen Z: Triptolide-mediated downregulation of FLIP(S) in hepatoma cells occurs at the post-transcriptional level independently of proteasome-mediated pathways. Med Oncol. 40:72022. View Article : Google Scholar : PubMed/NCBI

18 

Yao J, Jiang Z, Duan W, Huang J, Zhang L, Hu L, He L, Li F, Xiao Y, Shu B and Liu C: Involvement of mitochondrial pathway in triptolide-induced cytotoxicity in human normal liver L-02 cells. Biol Pharm Bull. 31:592–597. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, et al: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 24:4293–4300. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Zhai B and Sun XY: Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol. 5:345–352. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Liu Y, Xiao E, Yuan L and Li G: Triptolide synergistically enhances antitumor activity of oxaliplatin in colon carcinoma in vitro and in vivo. DNA Cell Biol. 33:418–425. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Nakazato T, Sagawa M and Kizaki M: Triptolide induces apoptotic cell death of multiple myeloma cells via transcriptional repression of Mcl-1. Int J Oncol. 44:1131–1138. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Chugh R, Sangwan V, Patil SP, Dudeja V, Dawra RK, Banerjee S, Schumacher RJ, Blazar BR, Georg GI, Vickers SM and Saluja AK: A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer. Sci Transl Med. 4:156ra1392012. View Article : Google Scholar : PubMed/NCBI

25 

Li J, Liu R, Yang Y, Huang Y, Li X, Liu R and Shen X: Triptolide-induced in vitro and in vivo cytotoxicity in human breast cancer stem cells and primary breast cancer cells. Oncol Rep. 31:2181–2186. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Wang X, Xu M, Peng Y, Naren Q, Xu Y, Wang X, Yang G, Shi X and Li X: Triptolide enhances lipolysis of adipocytes by enhancing ATGL transcription via upregulation of p53. Phytother Res. 34:3298–3310. 2020. View Article : Google Scholar : PubMed/NCBI

27 

Huang R, Guo F, Li Y, Liang Y, Li G, Fu P and Ma L: Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis. Phytomedicine. 92:1537392021. View Article : Google Scholar : PubMed/NCBI

28 

Liu Y, Chen F, Wang S, Guo X, Shi P, Wang W and Xu B: Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors. Cell Death Dis. 4:e9482013. View Article : Google Scholar : PubMed/NCBI

29 

Wu X, Chen S, Huang K and Lin G: Triptolide promotes ferroptosis by suppressing Nrf2 to overcome leukemia cell resistance to doxorubicin. Mol Med Rep. 27:172023. View Article : Google Scholar : PubMed/NCBI

30 

Deng Y, Chu X, Li Q, Zhu G, Hu J, Sun J, Zeng H, Huang J and Ge G: Xanthohumol ameliorates drug-induced hepatic ferroptosis via activating Nrf2/xCT/GPX4 signaling pathway. Phytomedicine. 126:1554582024. View Article : Google Scholar : PubMed/NCBI

31 

Luo L, Wang J, Zhao J, Yang B, Ma W and Lin J: Dental pulp stem cells derived exosomes inhibit ferroptosis via regulating the Nrf2-keap1/GPX4 signaling pathway to ameliorate chronic kidney disease injury. Tissue Cell. 93:1026702025. View Article : Google Scholar : PubMed/NCBI

32 

Li S, He Y, Chen K, Sun J, Zhang L, He Y, Yu H and Li Q: RSL3 drives ferroptosis through NF-κB pathway activation and GPX4 depletion in glioblastoma. Oxid Med Cell Longev. 2021:29150192021. View Article : Google Scholar : PubMed/NCBI

33 

Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A and Stockwell BR: Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 136:4551–4556. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI

35 

Fang X, Ardehali H, Min J and Wang F: The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol. 20:7–23. 2023. View Article : Google Scholar : PubMed/NCBI

36 

Shalev O, Repka T, Goldfarb A, Grinberg L, Abrahamov A, Olivieri NF, Rachmilewitz EA and Hebbel RP: Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo. Blood. 86:2008–2013. 1995. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Liu W, Wu G, Wang J, Wu S and Chen Z: Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis. Mol Med Rep 32: 202, 2025.
APA
Liu, W., Wu, G., Wang, J., Wu, S., & Chen, Z. (2025). Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis. Molecular Medicine Reports, 32, 202. https://doi.org/10.3892/mmr.2025.13567
MLA
Liu, W., Wu, G., Wang, J., Wu, S., Chen, Z."Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis". Molecular Medicine Reports 32.1 (2025): 202.
Chicago
Liu, W., Wu, G., Wang, J., Wu, S., Chen, Z."Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis". Molecular Medicine Reports 32, no. 1 (2025): 202. https://doi.org/10.3892/mmr.2025.13567
Copy and paste a formatted citation
x
Spandidos Publications style
Liu W, Wu G, Wang J, Wu S and Chen Z: Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis. Mol Med Rep 32: 202, 2025.
APA
Liu, W., Wu, G., Wang, J., Wu, S., & Chen, Z. (2025). Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis. Molecular Medicine Reports, 32, 202. https://doi.org/10.3892/mmr.2025.13567
MLA
Liu, W., Wu, G., Wang, J., Wu, S., Chen, Z."Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis". Molecular Medicine Reports 32.1 (2025): 202.
Chicago
Liu, W., Wu, G., Wang, J., Wu, S., Chen, Z."Co‑treatment with triptolide and RSL3 induces hepatocellular carcinoma cell apoptosis and ferroptosis". Molecular Medicine Reports 32, no. 1 (2025): 202. https://doi.org/10.3892/mmr.2025.13567
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team