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Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
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APOE suppresses osteosarcoma by modulating ferroptosis through the mTOR/Stat3 signaling pathway

Xiangyang Cheng1, Chong Bian1, Yiming Zhang1

  • 1Department of Orthopedics, Minhang Hospital, Fudan University, Minhang District, Shanghai, China.

Archives of Medical Science : AMS
|February 12, 2026
PubMed
Abstract

Insights

Apolipoprotein E (APOE) overexpression inhibits osteosarcoma (OS) growth by promoting ferroptosis and autophagy. This discovery offers a promising therapeutic target for treating this aggressive bone cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Osteosarcoma (OS) is a malignant bone tumor with limited therapeutic strategies.
  • The specific role of apolipoprotein E (APOE) in OS pathogenesis is not well understood.
  • Investigating novel therapeutic targets is crucial for improving OS treatment outcomes.

Purpose of the Study:

  • To elucidate the impact of APOE overexpression on osteosarcoma progression.
  • To explore the mechanisms by which APOE influences ferroptosis and autophagy in OS cells.
  • To evaluate the potential of APOE as a therapeutic target for osteosarcoma.

Main Methods:

  • Gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) networks identified APOE.
  • APOE was overexpressed in OS cell lines, and its effects on cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) were assessed.
  • Autophagy, ferroptosis, apoptosis, reactive oxygen species (ROS), intracellular iron levels, and the mTOR/Stat3 signaling pathway were analyzed using qRT-PCR, Western blot, and flow cytometry.
  • A mouse xenograft model was used for in vivo validation.

Main Results:

  • APOE overexpression significantly suppressed OS cell proliferation, invasion, migration, and EMT.
  • APOE enhanced autophagy and promoted apoptosis, evidenced by increased LC3B and Beclin1 expression and elevated ROS and Fe²⁺ levels.
  • APOE overexpression inhibited the mTOR and Stat3 signaling pathways, altered ferroptosis-related gene expression (upregulated TfR1, downregulated FPN, GPX4, SLC7A11), and reduced tumor growth in vivo.
  • Autophagy inhibition partially reversed the effects of APOE overexpression.

Conclusions:

  • APOE overexpression exerts anti-tumor effects in osteosarcoma by inducing ferroptosis and autophagy.
  • The mTOR/Stat3 signaling pathway is implicated in mediating the effects of APOE on OS.
  • APOE represents a potential therapeutic target for osteosarcoma treatment.
Keywords:
APOEautophagyferroptosismTOR/Stat3 signaling pathwayosteosarcoma

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