Skip to content
2000
image of SLC39A8 Inhibits Ferroptosis by Regulating the Β-Catenin/TCF4/ GPX4 Signaling in Osteosarcoma
file format pdf download PDF

Abstract

Introduction

SLC39A8 has been implicated in various cancers; however, its specific role in osteosarcoma (OS) remains poorly understood. This study aims to elucidate the functional significance of SLC39A8 in OS progression.

Methods

Using qRT-PCR and Western blot analysis, we analyzed SLC39A8 expression in osteosarcoma cells. Functional assays, including CCK-8, colony formation, and transwell assays, were employed to assess the impact of SLC39A8 on cell proliferation, migration, and invasion. Ferroptosis was evaluated by measuring lipid peroxidation, labile iron pool (LIP), Fe2+, malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), and GPX4 expression.

Results

Our results revealed that SLC39A8 is upregulated in osteosarcoma cells. The knockdown of SLC39A8 significantly suppressed cell proliferation, migration, and invasion while inducing ferroptosis, as evidenced by increased levels of LIP, Fe2+, MDA, and ROS, and decreased GSH and GPX4 expression. These effects were reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Furthermore, SLC39A8 overexpression activated the Wnt/β-catenin signaling pathway and upregulated GPX4 expression, effects that were abrogated by silencing β-catenin or TCF4. experiments confirmed that SLC39A8 knockdown inhibited tumor growth.

Discussion

SLC39A8 is a key zinc and iron transporter. Studies have reported that SLC39A8 was significantly dysregulated in some cancers and was associated with their prognosis. SLC39A8 has been identified as an iron metabolism- and ferroptosis-related gene related to the prognosis of esophageal squamous cell carcinoma. Our study showed that SLC39A8 promotes osteosarcoma cell proliferation, migration, and invasion while suppressing ferroptosis by regulating β-catenin signaling. Our study further indicated that LF3 reversed SLC39A8-mediated ferroptosis in osteosarcoma cells by reducing GPX4 expression. Although our study shows that SLC39A8 regulates the β-catenin signaling pathway, the upstream regulatory mechanism remains to be investigated.

Conclusion

Our findings demonstrate that SLC39A8 plays a pivotal role in osteosarcoma progression by modulating ferroptosis via the β-catenin/TCF4/GPX4 signaling pathways.

© 2026 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240400149251029112234
2026-01-09
2026-01-30

  • From This Site

    /content/journals/cmm/10.2174/0115665240400149251029112234
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmm/10.2174/0115665240400149251029112234/BMS-CMM-2025-161.html?itemId=/content/journals/cmm/10.2174/0115665240400149251029112234&mimeType=html&fmt=ahah

References

  1. Mirabello L. Troisi R.J. Savage S.A. Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009 115 7 1531 1543 10.1002/cncr.24121 19197972
    [Google Scholar]
  2. Beird H.C. Bielack S.S. Flanagan A.M. Osteosarcoma. Nat. Rev. Dis. Primers 2022 8 1 77 10.1038/s41572‑022‑00409‑y 36481668
    [Google Scholar]
  3. Gill J. Gorlick R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol. 2021 18 10 609 624 10.1038/s41571‑021‑00519‑8 34131316
    [Google Scholar]
  4. Khan F. Pandey P. Verma M. Emerging trends of phytochemicals as ferroptosis modulators in cancer therapy. Biomed. Pharmacother. 2024 173 116363 10.1016/j.biopha.2024.116363 38479184
    [Google Scholar]
  5. Pandey P. Pandey S. Ramniwas S. A review unveiling the ferroptosis-regulated cell signalling pathways in breast cancer to elucidate potent targets for cancer management. Curr. Pharm. Des. 2025 10.2174/0113816128343266241230045019 39901686
    [Google Scholar]
  6. Liu X. Du S. Wang S. Ferroptosis in osteosarcoma: A promising future. Front. Oncol. 2022 12 1031779 10.3389/fonc.2022.1031779 36457488
    [Google Scholar]
  7. Zang Z.S. Xu Y.M. Lau A.T.Y. Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8). Toxicol. Res. 2016 5 987 1002 10.1039/C5TX00424A
    [Google Scholar]
  8. Liu Y. Wei L. Zhu Z. Zinc transporters serve as prognostic predictors and their expression correlates with immune cell infiltration in specific cancer: A pan-cancer analysis. J. Cancer 2024 15 4 939 954 10.7150/jca.87880 38230214
    [Google Scholar]
  9. Shao Y. Jia H. Huang L. An original ferroptosis-related gene signature effectively predicts the prognosis and clinical status for colorectal cancer patients. Front. Oncol. 2021 11 711776 10.3389/fonc.2021.711776 34249766
    [Google Scholar]
  10. Zhao M. Li M. Zheng Y. Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma. J. Cancer 2022 13 5 1611 1622 10.7150/jca.68568
    [Google Scholar]
  11. Liu L. Hou Y. Hu J. SLC39A8/zinc suppresses the progression of clear cell renal cell carcinoma. Front. Oncol. 2021 11 651921 10.3389/fonc.2021.651921 33869056
    [Google Scholar]
  12. Liu Z. Huang J. Li D. Targeting ZIP8 mediated ferroptosis as a novel strategy to protect against the retinal pigment epithelial degeneration. Free Radic. Biol. Med. 2024 214 42 53 10.1016/j.freeradbiomed.2024.01.053 38309537
    [Google Scholar]
  13. Aierken Y. He H. Li R. Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells. Cardiovasc. Diabetol. 2024 23 1 186 10.1186/s12933‑024‑02224‑z 38812011
    [Google Scholar]
  14. Geng J. Wang Y. Lv F. Coumestrol facilitates apoptosis in colorectal cancer cells by interacting with ZIP8 protein via the ferroptosis pathway. J. Cancer 2024 15 14 4656 4667 10.7150/jca.94628 39006076
    [Google Scholar]
  15. Ding Y. Chen Q. Wnt/β-catenin signaling pathway: An attractive potential therapeutic target in osteosarcoma. Front. Oncol. 2025 14 1456959 10.3389/fonc.2024.1456959
    [Google Scholar]
  16. Wang Y. Zheng L. Shang W. Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer. Cell Death Differ. 2022 29 11 2190 2202 10.1038/s41418‑022‑01008‑w 35534546
    [Google Scholar]
  17. Li Z. Caron de Fromentel C. Kim W. RNA helicase DDX5 modulates sorafenib sensitivity in hepatocellular carcinoma via the Wnt/β-catenin–ferroptosis axis. Cell Death Dis. 2023 14 11 786 10.1038/s41419‑023‑06302‑0 38036507
    [Google Scholar]
  18. Tang J. Long G. Xiao L. Zhou L. USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization. Cell Death Dis. 2023 14 6 360 10.1038/s41419‑023‑05747‑7 37311739
    [Google Scholar]
  19. Luo L. Tang X. Liu L. ZCCHC4 promotes osteosarcoma progression by upregulating ITGB1. Crit. Rev. Eukaryot. Gene Expr. 2023 33 8 31 39 10.1615/CritRevEukaryotGeneExpr.2023047798 37606162
    [Google Scholar]
  20. Wei W. Hu Q. Li W. The role of ferroptosis signature in overall survival and chemotherapy of pancreatic adenocarcinoma. DNA Cell Biol. 2022 41 2 116 127 10.1089/dna.2021.0594 34898275
    [Google Scholar]
  21. a Liu Q. Wang K. The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin. Cell Biol. Int. 2019 43 11 1245 1256 10.1002/cbin.11121 30811078
    [Google Scholar]
  22. b Lei Y. Yang Q. Nie Y. Wan J. Deng M. Small-molecule inhibitor LF3 restrains the development of pulmonary hypertension through the Wnt/β-catenin pathway. Acta Biochim. Biophys. Sin. 2021 53 10 1277 1289 10.1093/abbs/gmab103 34410330
    [Google Scholar]
  23. Lu J. Xu Y. Xie W. Long noncoding RNA DLGAP1-AS2 facilitates Wnt1 transcription through physically interacting with Six3 and drives the malignancy of gastric cancer. Cell Death Discov. 2021 7 1 255 10.1038/s41420‑021‑00649‑z 34545072
    [Google Scholar]
  24. Qiu C. Liu T. Luo D. Novel therapeutic savior for osteosarcoma: The endorsement of ferroptosis. Front. Oncol. 2022 12 746030 10.3389/fonc.2022.746030 35402247
    [Google Scholar]
  25. Pandey P. Elsori D. Kumar R. Ferroptosis targeting natural compounds as a promising approach for developing potent liver cancer agents. Front. Pharmacol. 2024 15 1399677 10.3389/fphar.2024.1399677 38738178
    [Google Scholar]
  26. Alshammari N. Pandey P. Redhwan A. Unraveling the ferroptosis-inducing potential of methanol leaves extract of Prosopis juliflora via downregulation of SLC7A11 and GPX4 mRNA expression in A549 lung cancer cells. Curr. Med. Chem. 2025 32 7 1442 1456 10.2174/0109298673343133241011072425 39449336
    [Google Scholar]
  27. Wen R.J. Dong X. Zhuang H.W. Baicalin induces ferroptosis in osteosarcomas through a novel Nrf2/xCT/GPX4 regulatory axis. Phytomedicine 2023 116 154881 10.1016/j.phymed.2023.154881 37209607
    [Google Scholar]
  28. Chen M. Jiang Y. Sun Y. KDM4A-mediated histone demethylation of SLC7A11 inhibits cell ferroptosis in osteosarcoma. Biochem. Biophys. Res. Commun. 2021 550 77 83 10.1016/j.bbrc.2021.02.137 33689883
    [Google Scholar]
  29. Li X. Liu J. FANCD2 inhibits ferroptosis by regulating the JAK2/STAT3 pathway in osteosarcoma. BMC Cancer 2023 23 1 179 10.1186/s12885‑023‑10626‑7 36814203
    [Google Scholar]
  30. Aydemir T.B. Liuzzi J.P. McClellan S. Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells. J. Leukoc. Biol. 2009 86 2 337 348 10.1189/jlb.1208759 19401385
    [Google Scholar]
  31. Engelken J. Espadas G. Mancuso F.M. Signatures of evolutionary adaptation in quantitative trait loci influencing trace element homeostasis in liver. Mol. Biol. Evol. 2016 33 3 738 754 10.1093/molbev/msv267 26582562
    [Google Scholar]
  32. Yuan J. Liu T. Zhang Y. An iron metabolism-related gene signature for the prognosis of colon cancer. Front. Cell Dev. Biol. 2022 9 786684 10.3389/fcell.2021.786684 35118074
    [Google Scholar]
  33. Lei T. Qian H. Lei P. Ferroptosis-related gene signature associates with immunity and predicts prognosis accurately in patients with osteosarcoma. Cancer Sci. 2021 112 11 4785 4798 10.1111/cas.15131 34506683
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240400149251029112234
Loading
SLC39A8 Inhibits Ferroptosis by Regulating the Β-Catenin/TCF4/ GPX4 Signaling in Osteosarcoma
Bentham Science Publishers ; https://doi.org/10.2174/0115665240400149251029112234
/content/journals/cmm/10.2174/0115665240400149251029112234
/content/journals/cmm/10.2174/0115665240400149251029112234
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: migration ; Osteosarcoma ; proliferation ; SLC39A8 ; β-catenin/TCF4 signaling ; ferroptosis

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test