Work

APOE suppresses osteosarcoma by modulating ferroptosis through the mTOR/Stat3 signaling pathway

Year: 2025

Type: article

Abstract: Introduction Osteosarcoma (OS) is a highly malignant bone tumor with limited treatment options. The role of Apolipoprotein E (APOE) in OS remains unclear. This study explores the impact of APOE overexpression on OS, particularly its effects on ferroptosis and autophagy. Material and methods APOE was identified as a key gene through weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis of the GSE28424 dataset. APOE was overexpressed in OS cell lines to evaluate its effects on cell behavior. The role of autophagy was investigated using the autophagy inhibitor 3-MA. The involvement of ferroptosis and the mTOR/Stat3 signaling pathway was investigated utilizing Quantitative real-time reverse transcription PCR (qRT-PCR), Western blot (WB), and flow cytometry. A mouse xenograft model was employed to validate the in vitro results. Results APOE overexpression significantly inhibited OS cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT), with 3-MA partially reversing these effects. APOE overexpression also inhibited the mTOR and Stat3 expression, enhancing autophagy, as shown by increased LC3B-1, LC3B-2, and Beclin1 expression. Additionally, APOE overexpression promoted apoptosis, associated with increased reactive oxygen species (ROS) and intracellular Fe²⁺ levels, and altered ferroptosis-related gene expression, including upregulation of TfR1 and downregulation of FPN, GPX4, and SLC7A11. In vivo, APOE overexpression in a mouse xenograft model resulted in significantly smaller tumors, with changes in autophagy and ferroptosis markers consistent with in vitro findings. Conclusions APOE overexpression suppresses osteosarcoma growth by promoting ferroptosis and autophagy through the mTOR/Stat3 signaling pathway, highlighting its promise as a target for OS therapeutic intervention.

Source: Archives of Medical Science

DOI: 10.5114/aoms/203990

Authors: Xiangyang Cheng, Chong Bian, Yiming Zhang, Huijie Gu, Guangnan Chen, Liang Wu

Institution: Fudan University

Language: English

Topic: Ferroptosis and cancer prognosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,078