TPX2 promotes osteosarcoma progression by conferring ferroptosis resistance through the AURKA/NRF2 signaling axis
- 1Department of Orthopedic Surgery, Zhejiang Hospital, Hangzhou 310030, China
- 2Corresponding author.
Abstract
Background: Ferroptosis has emerged as a potential avenue for cancer therapy; however, the molecular mechanisms regulating ferroptosis resistance in osteosarcoma (OS) remain incompletely understood. This study aimed to investigate the role of targeting protein for Xklp2 ( TPX2 ) in OS progression and ferroptosis, focusing on the aurora kinase A ( AURKA ) / nuclear factor erythroid 2-related factor 2 ( NRF2 ) signaling axis. Methods: OS-related genes were screened from GSE16088 and GSE42352, followed by functional enrichment, protein-protein interaction (PPI), and receiver operating characteristic (ROC) analyses. TPX2 expression and function in OS cells were evaluated via quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, cell counting kit-8 (CCK-8), colony formation, and flow cytometry. Ferroptosis was evaluated in U2OS cells by cellular sensitivity to erastin/RSL3, reactive oxygen species (ROS) accumulation, Fe 2+ , malondialdehyde (MDA) levels, glutathione (GSH) redox status, and solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) expression. TPX2 and AURKA interaction in U2OS cells was probed using rescue and co-immunoprecipitation (Co-IP) experiments. The stability and ubiquitination level of NRF2 protein were detected using a cycloheximide (CHX) tracing assay and ubiquitination assay. Potential AURKA phosphorylation sites on NRF2 were further assessed using sequence-based kinase scoring. Results: TPX2 was abundantly expressed in OS and facilitated cell proliferation, clonogenicity, and G2-phase advancement. In U2OS cells, TPX2 depletion increased sensitivity to erastin and RSL3, ROS, Fe 2+ , and MDA levels and decreased GSH/GSSG, SLC7A11, and GPX4, which were partially reversed by ferrostatin-1. TPX2 interacted with AURKA, and rescue studies supported AURKA involvement in TPX2-dependent ferroptosis regulation. AURKA sustained NRF2 protein stability by reducing its ubiquitination and degradation. However, no NRF2 site reached the predefined AURKA scoring threshold. TPX2 overexpression had anti-ferroptotic effects, which were suppressed by NRF2 silencing. Conclusion: TPX2 contributes to OS cell proliferation and ferroptosis resistance in U2OS cells through an AURKA/NRF2 -associated mechanism. Direct NRF2 phosphorylation by AURKA remains unproven, and the ferroptosis mechanism requires validation in additional OS models.
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BibTeX
@article{liu2026tpx2,
title = {{TPX2 promotes osteosarcoma progression by conferring ferroptosis resistance through the AURKA/NRF2 signaling axis}},
author = {Huashun Liu and Lan Tang and Biao Chen and Jingtao Yu},
journal = {Journal of Bone Oncology},
year = {2026},
month = oct,
doi = {10.1016/j.jbo.2026.100807},
url = {https://doi.org/10.1016/j.jbo.2026.100807},
note = {CC BY},
}
RIS
TY - JOUR
TI - TPX2 promotes osteosarcoma progression by conferring ferroptosis resistance through the AURKA/NRF2 signaling axis
AU - Huashun Liu
AU - Lan Tang
AU - Biao Chen
AU - Jingtao Yu
PY - 2026
DA - 2026/10/31
JO - Journal of Bone Oncology
DO - 10.1016/j.jbo.2026.100807
UR - https://doi.org/10.1016/j.jbo.2026.100807
AB - Background: Ferroptosis has emerged as a potential avenue for cancer therapy; however, the molecular mechanisms regulating ferroptosis resistance in osteosarcoma (OS) remain incompletely understood. This study aimed to investigate the role of targeting protein for Xklp2 ( TPX2 ) in OS progression and ferroptosis, focusing on the aurora kinase A ( AURKA ) / nuclear factor erythroid 2-related factor 2 ( NRF2 ) signaling axis. Methods: OS-related genes were screened from GSE16088 and GSE42352, followed by functional enrichment, protein-protein interaction (PPI), and receiver operating characteristic (ROC) analyses. TPX2 expression and function in OS cells were evaluated via quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, cell counting kit-8 (CCK-8), colony formation, and flow cytometry. Ferroptosis was evaluated in U2OS cells by cellular sensitivity to erastin/RSL3, reactive oxygen species (ROS) accumulation, Fe 2+ , malondialdehyde (MDA) levels, glutathione (GSH) redox status, and solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) expression. TPX2 and AURKA interaction in U2OS cells was probed using rescue and co-immunoprecipitation (Co-IP) experiments. The stability and ubiquitination level of NRF2 protein were detected using a cycloheximide (CHX) tracing assay and ubiquitination assay. Potential AURKA phosphorylation sites on NRF2 were further assessed using sequence-based kinase scoring. Results: TPX2 was abundantly expressed in OS and facilitated cell proliferation, clonogenicity, and G2-phase advancement. In U2OS cells, TPX2 depletion increased sensitivity to erastin and RSL3, ROS, Fe 2+ , and MDA levels and decreased GSH/GSSG, SLC7A11, and GPX4, which were partially reversed by ferrostatin-1. TPX2 interacted with AURKA, and rescue studies supported AURKA involvement in TPX2-dependent ferroptosis regulation. AURKA sustained NRF2 protein stability by reducing its ubiquitination and degradation. However, no NRF2 site reached the predefined AURKA scoring threshold. TPX2 overexpression had anti-ferroptotic effects, which were suppressed by NRF2 silencing. Conclusion: TPX2 contributes to OS cell proliferation and ferroptosis resistance in U2OS cells through an AURKA/NRF2 -associated mechanism. Direct NRF2 phosphorylation by AURKA remains unproven, and the ferroptosis mechanism requires validation in additional OS models.
SN - 2212-1374
ER -