Hypoxia-inducible factor-1α can reverse the Adriamycin resistance of breast cancer adjuvant chemotherapy - Research Article

Q: How can ferroptosis be reversed to reduce Adriamycin-resistant survival?

Overexpressing HIF1α in ADR-resistant cells increases TFRC, Fe2+, and MDA. After ADR treatment, cell survival decreases, and ferroptosis can be reversed by combining Fer-1, consistent with a TFRC-mediated ferroptosis mechanism.

Sep 21, 2026

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Breast cancer is a common malignant tumor in women, and ferroptosis is tightly linked to breast cancer biology and therapy resistance. This study examines how the transferrin receptor (TFRC) and its upstream transcription factor hypoxia-inducible factor-1α (HIF1α) influence neoadjuvant therapy efficacy. Clinical sequencing identified TFRC as a key differentially expressed gene, elevated in tumor tissues, reduced in Adriamycin-resistant samples. Findings connect IREB2 with TFRC to regulate ferroptosis, with HIF1α positively modulating TFRC. In sensitive TAC regimens, iron ion (Fe2+) and malondialdehyde (MDA) increased versus resistant groups. HIF1α upregulation restored ferroptosis markers and reduced cell survival after ADR, supporting a mechanism for reversing chemotherapy resistance via TFRC-driven ferroptosis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

Role of ADR and resistance mechanisms

Iron metabolism and ferroptosis in tumors

TFRC and HIF1α as regulatory axis

DOI: 10.1096/fj.202401119R RESEAR CH ARTICLE Hypoxia-inducible factor-1α can reverse the Adriamycin resistance of breast cancer adjuvant chemotherapy by upregulating transferrin receptor and activating ferroptosis Xiaojie Yu1 | Qingqun Guo1 | Haojie Zhang1 | Xiaohong Wang2 | Yong Han1 | Zhenlin Yang1 1Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, P.R. China 2Department of Breast Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, P.R. China Correspondence Yong Han and Zhenlin Yang, Department of Thyroid Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China. Email: [hanyong2021@126.com](hanyong2021@126.com) and [ikb0607@163.com](ikb0607@163.com) Funding information National Natural Science Foundation of China, Grant/Award Number: 81902702; Natural Science Foundation of Shandong Province, Grant/ Award Number: ZR2023MH115 and ZR2017LH072; National Key Research and Development Project, Grant/Award Number: 2018YFC0114705 Abstract Breast cancer is a common malignant tumor in women. Ferroptosis, a programmed cell death pathway, is closely associated with breast cancer and its resistance. The transferrin receptor (TFRC) is a key factor in ferroptosis, playing a crucial role in intracellular iron accumulation and the occurrence of ferroptosis. This study investigates the influence and significance of TFRC and its upstream transcription factor hypoxia-inducible factor-1α (HIF1α) on the efficacy of neoadjuvant therapy in breast cancer. The differential gene obtained from clinical samples through genetic sequencing is TFRC. Bioinformatics analysis revealed that TFRC expression in breast cancer was significantly greater in breast cancer tissues than in normal tissues, but significantly downregulated in Adriamycin (ADR)-resistant tissues. Iron-responsive element-binding protein 2 (IREB2) interacts with TFRC and participates in ferroptosis. HIF1α, an upstream transcription factor, positively regulates TFRC. Experimental results indicated higher levels of ferroptosis markers in breast cancer tissue than in normal tissue. In the TAC neoadjuvant regimen-sensitive group, iron ion (Fe2+) and malondialdehyde (MDA) levels were greater than those in the resistant group (all p < .05) . Expression levels ofTFRC, IREB2, FTH1, and HIF1α were higher in breast cancer tissue compared to normal tissue. Additionally, the expression of the TFRC protein in the TAC neoadjuvant regimen-sensitive group was significantly higher than that in the resistant group (all p < .05), while the difference in the level of expression of IREB2 and FTH1 between the sensitive and resistant groups was not | Abbreviations: ADR, adriamycin; BCA, bicinchoninic acid; CCK-8, cell counting kit-8; CR, complete response; DAB, diaminobenzidine; DEGs, differentially expressed genes; ECL, electrochemical luminescence; Fe2+, iron ion; Fer-1, ferroptosis inhibitor; FTH1, ferritin heavy chain 1; GSH, glutathione; HIF1α, hypoxia-inducible factor-1α; IC50, cell viability and the half-maximal inhibitory concentration; IREB2, iron-responsive element-binding protein 2; IRES, iron-responsive element; KEGG, kyoto encyclopedia of genes and genomes; MDA, malondialdehyde; OD, optical density; OE-HIF1α, overexpressing HIF1α; PR, partial response; sh-HIF1α, downregulating the expression of HIF1α; sh-NC, nonsense sequence; TAC, docetaxel + adriamycin + cyclophosphamide; TFRC, transferrin receptor; WHO, World Health Organization.
Han Yong and Zhenlin Yang are co-corresponding authors. | | --- | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Author(s) . The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Soc

FAQs

How can ferroptosis be reversed to reduce Adriamycin-resistant survival?

Overexpressing HIF1α in ADR-resistant cells increases TFRC, Fe2+, and MDA. After ADR treatment, cell survival decreases, and ferroptosis can be reversed by combining Fer-1, consistent with a TFRC-mediated ferroptosis mechanism.

Sep 21, 2026

Uploaded by Evangeline