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PRDX1 depletion predisposes to ferroptosis through inhibiting the cAMP pathway in B-cell acute lymphoblastic leukemia

Cancer Gene Therapy (2025)Cite this article

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Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy commonly found in pediatric patients. This study aims to screen hub genes in B-ALL and elucidate the role of peroxiredoxin 1 (PRDX1) in the modulation of ferroptosis. Bioinformatics analyses were conducted to identify pivotal genes in the GSE17703 and GSE48558 datasets. The biological effects of PRDX1 deletion in B-ALL cells and the xenograft tumor were evaluated using a series of functional assays. Ferroptosis was induced in B-ALL cells using erastin. Transcriptome sequencing was performed on Nalm-6 cells before and after PRDX1 knockdown. Forskolin was employed to explore the role of PRDX1 in the cyclic adenosine monophosphate (cAMP) pathway. Four pivotal genes were identified, with two genes upregulated and two downregulated. Depletion of PRDX1 suppressed the proliferative, migratory, and invasive abilities of B-ALL cells, whereas PRDX1 overexpression exerted the opposite effects. PRDX1 silencing promoted erastin-induced ferroptosis, including elevated levels of COX2, ACSL4, ferrous ions, ROS, and MDA, while reducing GPX4, GSH, and SOD levels. PRDX1 knockdown further reduced the viability of B-ALL cells treated with the ferroptosis activator ML210, and treatment with the ferroptosis inhibitor liproxstatin-1 significantly reversed the suppressive effect of PRDX1 knockdown on xenograft tumor growth. Mechanically, PRDX1 deletion triggered ferroptosis in B-ALL cells by inhibiting the cAMP pathway. PRDX1 deficiency modulates ferroptosis in B-ALL cells by blocking the cAMP pathway, which offer a novel perspective on the pathogenesis of B-ALL.

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Fig. 1: Analysis and verification of hub genes.
Fig. 2: PRDX1 and HSPB1 regulate each other’s expression and modulate CFLAR and MAP3K5 mRNA levels in B-ALL cell lines.
Fig. 3: PRDX1 silencing suppresses proliferation, migration, and invasion of B-ALL cells.
Fig. 4: PRDX1 overexpression promotes the malignant phenotype of B-ALL cells.
Fig. 5: PRDX1 depletion predisposes ferroptosis of B-ALL cells.
Fig. 6: Downregulation of PRDX1 attenuates tumorigenicity of B-ALL and facilitates ferroptosis in vivo.
Fig. 7: Analysis of potential pathways involved in B-ALL.
Fig. 8: PRDX1 knockdown affects ferroptosis via the cAMP pathway in B-ALL cells.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Publicly available gene expression datasets GSE17703 and GSE48558 were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).

Code availability

The R code for all bioinformatics analyses in this study is available by contacting the corresponding authors.

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Funding

1. Sichuan Science and Technology Program (Project No.: 2022YFS0622; 2022YFS0622-A2); 2. Doctoral Research Initiation Fund of Affiliated Hospital of Southwest Medical University (Project No. :22152); 3. Research Project of Southwest Medical University (Project No. : 2021ZKQN062); 4. Luzhou Science and Technology Program (Project No. : 2022-SYF-44).

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Authors and Affiliations

  1. Department of Pediatrics, Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou City, Sichuan, China

    FangFang Zhong, Yan Zeng, Jing Liu, Qulian Guo & Ping Wen

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  1. FangFang Zhong
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  2. Yan Zeng
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  3. Jing Liu
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  4. Qulian Guo
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Contributions

FangFang Zhong: conception and design of the research, acquisition of data, revision of manuscript for important intellectual content; Yan Zeng and Jing Liu: acquisition of data, performing the experiment, drafting the manuscript; Qulian Guo and Ping Wen: analysis and interpretation of data; performing the experiment. All the authors read and approved the manuscript.

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Correspondence to FangFang Zhong or Ping Wen.

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All the animal experiments were approved by the Animal Care and Use Committee of the Affiliated Hospital of Southwest Medical University and were conducted in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals. The study is reported in accordance with ARRIVE guidelines.

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Zhong, F., Zeng, Y., Liu, J. et al. PRDX1 depletion predisposes to ferroptosis through inhibiting the cAMP pathway in B-cell acute lymphoblastic leukemia. Cancer Gene Ther (2025). https://doi.org/10.1038/s41417-025-00992-8

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