TFRC promotes ferroptosis to suppress breast cancer bone metastasis via the activation of HIF-1 pathway

Sep 22, 2026

Bone metastasis remains a major clinical challenge in breast cancer. Ferroptosis, an iron-dependent form of cell death, may modulate metastatic behavior, but the regulatory role of the transferrin receptor (TFRC) is not well defined. Transcriptome sequencing and protein-protein interaction analyses identified ferroptosis-related differential genes and hub genes. Functional validation used cell and intratibial mouse models, demonstrating that TFRC promotes ferroptosis through HIF-1α activation and suppresses bone metastasis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

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Introduction

Abstract

Methods

Results

Conclusion

Liu et al. Breast Cancer Research (2026) 28:104 Breast Cancer Research [https://doi.org/10.1186/s13058-026-02269-w](https://doi.org/10.1186/s13058-026-02269-w) RESEARCH Open Access TFRC promotes ferroptosis to suppress breast cancer bone metastasis via the activation of HIF-1 pathway Lulin Liu 1,2,3†, Yan Gao 1†, Dongmin Yu4, Deping Li5, Sheng Liu2, Chunlei He2, Chunlin Xiao2, Yongjun Ye2, Kai Zhao2, Fangtian Xu2 andYanming Hao 1* Abstract Background Breast cancer with bone metastasis remains a significant clinical challenge. Ferroptosis, an irondependent cell death process, may influence metastasis. However, the role of key regulators like transferrin receptor (TFRC) is unclear. Methods Transcriptome sequencing identified ferroptosis-related differential ly expressed genes (DEGs) in tibial tumors from a breast cancer mouse model with bone metastasis versus breast cancer cells. Hub genes were identified via protein-protein interaction network analysis. The function ofTFRC was validated in vitro (MCF-7 and MDA-MB-231) through gain/loss-of-function studies combined with ferroptosis modulators (Erastin, Ferrostatin-1) and in a BALB/c nude mouse intratibial model. Cell apoptosis, proliferation, invasion, and migration were evaluated by flow cytometry, cell-counting kit-8, Transwell, and wound healing assays, respectively. Ferroptosis markers and epithelialmesenchymal transition-related proteins were assessed. The involvement of the hypoxia-inducible factor-1 (HIF-1) pathway was investigated using the HIF-1α inhibitor PX-478 . Results Bioinformatics identified 22 ferroptosis-related DEGs, with TFRC among the top 10 hub genes significantly downregulated in bone metastasis, a finding corroborated in human clinical specimens. Overexpressing TFRC in vivo suppressed tumor growth, upregulated E-cadherin, downregulated N-cadherin, and promoted ferroptosis. In vitro, TFRC overexpression consistently inhibited malignant phenotypes and induced ferroptosis in both cell lines, effects reversible by ferroptosis inhibition. Conversely, ferroptosis activation upregulated TFRC expression, and TFRC knockdown attenuated cellular sensitivity to ferroptosis inducers, indicating a reciprocal regulatory relationship. Mechanistically, HIF-1 pathway was identified as the downstream pathway ofTFRC, and TFRC overexpression upregulated HIF-1α . PX-478 attenuated TFRC-mediated ferroptosis induction and suppression of malignancy. Conclusion TFRC inhibits bone metastasis in breast cancer by promoting ferroptosis via HIF-1α activation, highlighting its potential as a therapeutic target. Keywords TFRC, Breast cancer bone metastasis, Ferroptosis, HIF-1 signaling pathway †Lulin Liu and Yan Gao are Co-first authors. *Correspondence: Yanming Hao [a3878072@163.com](a3878072@163.com) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Liu et al. Breast Cancer

FAQs

What is the main objective of this study?

To determine whether TFRC promotes ferroptosis and suppresses breast cancer bone metastasis through activation of the HIF-1 pathway.

How did the researchers identify ferroptosis-related key regulators?

They performed transcriptome sequencing to find ferroptosis-related differential genes and used protein-protein interaction network analysis to identify hub genes.

What evidence supports TFRC’s role in inhibiting metastasis?

TFRC overexpression suppressed tumor growth in vivo and inhibited malignant phenotypes in vitro, while ferroptosis modulation showed that these effects were reversible by ferroptosis inhibition.

Sep 22, 2026

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