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PRDX1 knockdown promotes erastin-induced ferroptosis and impedes diffuse large B-cell lymphoma development by inhibiting the MAPK/ERK pathway

BMC Cancer volume 25, Article number: 806 (2025) Cite this article

Abstract

Aim

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma and DLBCL cells are highly sensitive to ferroptosis. The purpose of this research was to evaluate the role and molecular mechanism of peroxiredoxin 1 (PRDX1) on ferroptosis in DLBCL.

Methods

The expression of PRDX1 in DLBCL tissues and cells was detected using bioinformatics analysis and reverse transcription quantitative PCR. The impacts of PRDX1 on DLBCL cell proliferation, apoptosis, migration, invasion, and ferroptosis were assessed through a series of in vitro experiments. A xenograft tumor model was constructed to verify the roles of PRDX1 in vivo. Transcriptome sequencing was conducted to identify PRDX1-mediated signaling pathways. Anisomycin, an agonist of mitogen-activated protein kinase (MAPK), was used to explore the modulation of PRDX1 on the MAPK pathway.

Results

PRDX1 expression was upregulated in DLBCL. PRDX1 knockdown inhibited DLBCL cell proliferation, migration, and invasion, promoted apoptosis, and suppressed xenograft tumor growth. PRDX1 knockdown boosted erastin-induced ferroptosis by increasing the levels of iron and MDA, while decreasing the levels of GSH. It also promoted COX2 protein expression and inhibited GPX4 and SLC7A11 protein levels. PRDX1 knockdown reduced the phosphorylation levels of MEK and ERK both under conditions with or without erastin induction. The MAPK/ERK pathway agonist anisomycin, significantly reversed the inhibitory effects of PRDX1 knockdown on the malignant behaviors of DLBCL cells and the promotion of ferroptosis.

Conclusion

PRDX1 knockdown facilitates erastin-induced ferroptosis and obstacles DLBCL progression by inhibiting the MAPK/ERK pathway, offering a potential treatment strategy for DLBCL treatment.

Peer Review reports

Introduction

Diffuse large B cell lymphoma (DLBCL) is the most prevalent form of lymphoma among adults globally, accounting for approximately one-third of annual non-Hodgkin lymphoma (NHL) cases [1]. DLBCL demonstrates heterogeneity and aggressiveness, with high malignancy, rapid progression, and poor prognosis [2]. Immunochemotherapy, specifically the R-CHOP regimen (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone), is the main treatment for DLBCL, resulting in a 5-year overall survival rate of about 65%, although around 35% of cases still progress to relapsed or refractory disease [3]. Major therapeutic challenges in DLBCL treatment stem from its molecular heterogeneity and resistance to apoptosis [4, 5]. Consequently, an in-depth exploration of the mechanisms driving DLBCL tumorigenesis is critical for advancing therapeutic development.

The Peroxiredoxin family (PRDXs) is a superfamily of thiol-dependent peroxidases consisting of PRDX1 to PRDX6, with PRDX1 exhibiting the highest abundance in a variety of mammalian tissues [6]. PRDX1 contributes to the maintenance of redox balance by eliminating reactive oxygen species (ROS) and thiyl radicals [7, 8]. Emerging research has demonstrated that PRDX1 is engaged in the progression of multiple tumors. PRDX1 directly interacts with the actin-binding protein Cofilin and inhibits the phosphorylation of its Ser3 site, facilitating invasion and metastasis of oral squamous cell carcinoma cells and enhancing lymph node metastasis [9]. Knockdown of PRDX1 diminishes non-small-cancer lung carcinoma proliferation and enhances apoptosis by activating Wnt/β-Catenin signaling [10]. Conversely, PRDX1 is lowly expressed in tumor tissues of patients with osteosarcoma and fibrosarcoma, and PRDX1 restricts the invasion and metastasis of these tumor cells [11]. PRDX1 is also closely linked to the immunoglobulin production capacity of cells, with elevated levels observed in multiple myeloma cases, potentially identifying it as a functional marker for plasma cells [12]. Moreover, Wu et al. revealed that PRDX1 expression is upregulated in two NHL cell lines and primary lymphoma tissues [13]. Recently, PRDX1 has been identified as a ferroptosis-related gene in DLBCL [14]. However, the specific functions and mechanisms of PRDX1 in the DLBCL remain to be clarified.

Resistance of lymphoma cells to apoptosis significantly contributes to the ineffectiveness of multiagent chemotherapy [15]. Unlike their resistance to apoptosis, DLBCL cells exhibit strong sensitivity to ferroptosis, making the induction of ferroptosis a potentially effective treatment option for managing DLBCL patients unresponsive to conventional chemotherapy [16]. Ferroptosis is an iron-dependent form of cell death that is triggered by iron and ROS accumulation [17]. A complex network of molecular mechanisms plays a role in modulating ferroptosis in DLBCL. Zhang et al. revealed that elevated TCP1 expression heightens the vulnerability of germinal centre B-cell-like tumor cells to ferroptosis in DLBCL [18]. PAQR3 facilitates ferroptosis in DLBCL by restraining the LDLR-mediated PI3K/AKT pathway [19]. Through the NF-κB/STAT3/GPX4 signaling axis, FASN promotes Adriamycin resistance in DLBCL by blocking ferroptosis [20]. These results indicate that ferroptosis is pivotal in the DLBCL development and provides a theoretical foundation for targeting ferroptosis in DLBCL treatment. Despite these insights, the mechanisms of ferroptosis in DLBCL remain partially understood and require further investigation. PRDX1, which reduces ROS and limits lipid peroxidation, may inhibit ferroptosis when highly expressed, whereas reduced PRDX1 level could increase oxidative stress and promote ferroptosis [21]. Moreover, earlier research has shown that PRDX1 is implicated in the modulation of ferroptosis in several tumors, such as hepatocellular carcinoma [22]. However, the involvement and molecular pathways of PRDX1 concerning ferroptosis in DLBCL have not been elucidated.

The objective of this study was to evaluate the correlation between PRDX1 expression and the development of DLBCL, with a particular focus on ferroptosis. Here, we explored the functions of PRDX1 in OCI-Ly3 and DB cell proliferation, apoptosis, migration, invasion, and ferroptosis, as well as in xenograft tumor growth. Furthermore, the downstream target MAPK/ERK signaling pathway was identified by transcriptome sequencing. Collectively, we found that PRDX1 knockdown may promote erastin-induced ferroptosis and DLBCL progression by blocking the MAPK/ERK pathway, which provides a theoretical foundation for addressing DLBCL.

Materials and methods

PRDX1 expression were analyzed by bioinformatics methods

PRDX1 expression in DLBCL was explored utilizing the Expression Analysis function in the Expression-DIY section of the GEPIA2 database (http://gepia2.cancer-pku.cn/#analysis). Additionally, the expression of PRDX1 was evaluated in tumor and normal tissues using the microarray dataset GSE95290 in the Oncomine database (https://www.oncomine.com/).

Gene set enrichment analysis (GSEA)

Gene set enrichment analysis (GSEA) was performed to identify significantly enriched hallmark gene sets associated with the biological characteristics using clusterProfiler package. Hallmark gene sets from the Molecular Signatures Database were utilized, and significance was assessed using 1,000 gene permutations.

Cell culture and treatment

Human B lymphocyte (GM12878) and human DLBCL cell lines (OCI-Ly3 and DB) were purchased from the Icellbioscience Biotechnology Co., Ltd. (Shanghai, China). GM12878 and DB cells were grown in RPMI-1640 (Hyclone, Logan, UT, USA) with 10% fetal bovine serum (FBS, Gibco BRL Co., Ltd., Houston, TX, USA) and 1% antibiotics (Thermo Fisher Scientific, MA, USA), at 37℃ in 5% CO2. OCI-Ly3 was cultivated in DMEM medium (Hyclone) under the same culture conditions.

PRDX1-targeting small interfering RNA (siRNA) and a negative control si-NC were synthesized by GenePharma (Shanghai, China). Transfection of OCI-Ly3 and DB cells was performed with 50 nM siRNAs via Lipofectamine 3000 (Thermo Fisher Scientific) in accordance with the instructions of manufacturers. Cells were harvested for RT-PCR analysis after 24 h of transfection to analyze the knockdown efficiency. The siRNA sequences are shown in Supplementary Table 1. To induce ferroptosis, OCI-Ly3 and DB cells were exposed to erastin (10 µM, Selleck Chemicals, Houston, TX, USA) for 24 h with DMSO treatment alone as the control group. In addition, the MAPK activator anisomycin (Selleck Chemicals) was solubilized in DMSO and OCI-Ly3 and DB cells received a 48-h treatment with anisomycin (0.2 µM). Furthermore, cells were treated with BVD-523 (Ulixertinib, Selleck Chemicals), a MEK inhibitor, at a concentration of 10 µM for 24 h.

Reverse transcription quantitative PCR (RT-qPCR)

Total RNA from DLBCL cells was isolated applying TRIzol reagent (Thermo Fisher Scientific) and then cDNA was synthesized with High Capacity cDNA Reverse Transcription Kit (Applied Bio-systems, California, USA). Gene amplification levels were quantified using the ABI7500 instrument (Applied Biosystems, Shanghai, China). Relative mRNA levels were determined employing the 2-ΔΔCt method and GAPDH was used as a reference for normalization. Supplementary Table 1 contains all the primer sequences.

Cell counting kit (CCK)-8 assay

The proliferation of cells was evaluated utilizing the CCK-8 kit (Beyotime, Shanghai, China) following the manufacturer’s guidelines. Briefly, DLBCL cells (5 × 10³ cells/well) were inoculated into 96-well plates and cultured for 24, 48, 72 h, and 96 h respectively. Then, CCK-8 solution (10 µL) was supplemented to each well. After 1 h of incubation at 37°C, the absorbance at 450 nm wavelength was detected for each well with a microplate reader (DALB, Shanghai, China).

Flow cytometry

Apoptosis was evaluated by the FITC Annexin V Apoptosis Detection Kit (BD Pharmingen, NJ, USA). Briefly, A mixture of 5 µL of FITC Annexin V and 5 µL of PI were incorporated into 100 µL of cell suspension (1 × 105 cells) and incubated in the dark for 15 min. Apoptosis was assessed by a flow cytometry and apoptosis rate was measured with FlowJo software.

Transwell assay

To analyze cell migration and invasion, the Transwell assay was utilized. 100 µL of serum-free medium (1 × 105 cells) was introduced into the upper transwell chamber. A total of 600 uL complete medium with 20% FBS was introduced into the lower chamber. After 24 h of incubation, cells migrating to the lower surface were fixed with methanol. Subsequently, cells were stained with 0.1% crystal violet for 30 min. The invasion experiments utilized chambers that had been pre-coated with Matrigel (BD Biosciences, San Jose, CA), and the procedures above were repeated.

Iron assay

Cells (1 × 10⁵ cells/well) were plated in a 6-well plate. Iron content in OCI-Ly3 and DB cells was measured using Iron Colorimetric Assay Kit (E1042, Beijing Applygen Technologies) in accordance with the manufacturer’s guidelines. The absorbance at 593 nm was recorded with a microplate reader (DALB).

Malondialdehyde (MDA) assay

MDA content in cells was quantified with an MDA Assay Kit (Abcam, Cambridge, UK, ab118970). In brief, cell lysis was performed with MDA lysis buffer (0.1 mol/L MDA standard solution) containing butylated hydroxytoluene, and samples were centrifuged at 16,000 × g for 10 min at 4°C. After incorporating thiobarbituric acid, the samples were subjected to incubation at 95°C for 10 min, with absorbance readings taken at 532 nm.

Glutathione (GSH) assay

The concentration of GSH in cells was assessed with the GSH assay kit (CS0260; Sigma, St. Louis, Missouri, USA) in line with the manufacturer’s recommendations. Cells were lysed in GSH assay buffer and cell lysates were subjected to centrifugation at 13,200 rpm for 10 min at 4°C. Subsequently, 50 µL of the GSH assay mixture was incorporated into each sample well and incubated for 60 min at room temperature in the dark. The measurement of GSH was conducted using a kinetic assay and absorbance at 412 nm was measured.

Western blot

RIPA buffer was used to lyse cells and tumor tissues, after which total protein concentrations were quantified with a BCA assay kit (Solarbio, Beijing, China). Each protein sample was subjected to separation via 10% SDS-PAGE and subsequently transferred onto PVDF membranes (Millipore, Billerica, MA, USA). The membranes were blocked with 5% skimmed milk and then treated with PRDX1 (Abcam, Cambridge, UK, ab109506) COX2 (Abcam, ab179800), GPX4 (Abcam, ab125066), ERK (Cell Signaling Technology, CST, Danvers MA, USA, 9212), Phospho-ERK (p-ERK, CST, 4370), MEK (CST, 9122), p-MEK (CST, 9121), SCL7A11 (Abcam, ab307601), and GAPDH (Abcam, ab8245) antibodies overnight at 4°C. Each antibody was diluted to a concentration of 1:2000. Proteins were detected with enhanced chemiluminescence (Vazyme, Nanjing, China) and protein bands were measured by ImageJ software.

Transcriptome sequencing

After isolating total RNA from OCI-Ly3 cells in the si-PRDX1 and si-NC group, the polyadenylated mRNA was purified utilizing Oligo(dT) beads, and RNA was fragmented to approximately 300 base pairs. Using random hexamer primers, cDNA was synthesized from RNA through reverse transcription. Library quality was assessed via the Agilent 2100 Bioanalyzer, and paired-end sequencing was performed on the Illumina platform. The expression levels of genes were normalized and determined as fragments per kilobase of transcript per million mapped reads (FPKM). Differentially expressed genes (DEGs) were screened with the DESeq R package with thresholds of|log2 FC| > 1 and P < 0.05. Visualization of these DEGs was performed by generating a volcano plot with the ggplot2 package and a heatmap with the pheatmap package. The analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was carried out with the clusterProfiler package.

Construction of stable PRDX1 knockdown cell lines

OCI-LY3 cells were infected with lentivirus vectors encoding either short hairpin PRDX1 (lv-PRDX1) or its empty lentiviral vector (lv-NC; OBIO, Shanghai, China). Cells with stable transfection were selected by treatment with 5 µg/ml puromycin.

Xenograft model

The animal experiment was conducted following the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Male BALB/c nude mice (aged 6–8 weeks, weighing18-20 g) were purchased from the SPF Biotechnology Co. (Beijing, China). Mice were kept in specific pathogen-free conditions with a 12-h light/dark cycle and were given unrestricted access to a certified standard diet and tap water. The mice were randomly allocated to two groups (6 per group): the lv-NC group and the lv-PRDX1 group. For the construction of subcutaneous xenograft models, a total of 5 × 106 OCI-Ly3 cells stably transduced with the lv-PRDX1 or lv-NC vectors were administered via subcutaneous injection into the mice [23]. Tumor size was monitored every seven days with a vernier caliper. Tumor volume was determined using the formula: volume (mm³) = (width ² × length)/2. After 28 days, mice were euthanized by inhalation of isoflurane and tumor tissues and serum were collected for subsequent experiments. In addition, tumor growth curves were plotted and tumor tissues were weighed.

Immunohistochemical staining (IHC)

The paraffin-embedded sections underwent dewaxing, rehydration, and antigen retrieval with 10 mmol/L EDTA. To inactivate endogenous peroxidase, the sections were incubated at 37°C in a solution of 0.3% H₂O₂. The sections were blocked with normal goat serum for 60 min, followed by incubation with anti-GPX4 antibody (1:500, Abcam, ab125066) and anti-ki67 antibody (1:500, Abcam, ab15580) overnight at 4°C. The sections were treated with a secondary antibody (Abcam) at 37°C for 60 min. Sections were stained with 3,3-diaminobenzidine (DAB) for visualization and then processed with hematoxylin and eosin staining. Following decolorization, dehydration, and sealing, the sections were observed utilizing a microscope (Olympus, Tokyo, Japan).

Statistical analysis

Every experiment was carried out at least three times. GraphPad Prism 9 was utilized for statistical analysis, and the data are represented as mean ± SD. Comparisons between two groups were made with the t-test, and one-way ANOVA was utilized for multi-group analyses, followed by Tukey’s post hoc test for pairwise comparisons. Statistical significance was determined with a threshold of P < 0.05.

Results

PRDX1 knockdown reduces DLBCL cell proliferation, migration, and invasion and promotes apoptosis

We explored PRDX1 expression in DLBCL. In the GEPIA2 database, PRDX1 expression level was found to be elevated in patients with DLBCL compared to normal controls (Fig. 1A). Meanwhile, based on the GSE95290 dataset in the Oncomine database, it was noted that PRDX1 expression was increased in DLBCL tissues relative to normal tissues (Fig. 1B). Then, the PRDX1 expression in human B lymphocytes (GM12878) and DLBCL cells (OCI-Ly3 and DB) was assessed using RT-qPCR. The findings showed that compared to GM12878 cells, PRDX1 expression was significantly elevated in OCI-Ly3 and DB cells (Fig. 1C). The above findings indicate that PRDX1 is overexpressed in DLBCL. GSEA was conducted on based on the GSE95290 dataset and the results identified significant enrichment of the E2F targets, MYC targets, and TNF-α/NF-κB signaling (Supplementary Fig. 1). To see how PRDX1 impacted DLBCL, three PRDX1 knockdown siRNAs were constructed and were transfected in OCI-Ly3 and DB cells. RT-qPCR and western blot assays showed that the expression level of PRDX1 was significantly reduced in the si-PRDX1-1, si-PRDX1-2, and si-PRDX1-3 groups compared to the si-NC group (Fig. 1D and E). We then chose si-PRDX1-1 for subsequent exploration. CCK-8 assays revealed that PRDX1 knockdown diminished the OCI-Ly3 and DB cell proliferation in comparison to the si-NC group (Fig. 1F). According to flow cytometry findings, PRDX1 knockdown facilitated cell apoptosis in OCI-Ly3 and DB cells (Fig. 1G). Additionally, the Transwell assay outcomes indicated that PRDX1 knockdown significantly decreased cell migration and invasion relative to the si-NC group (Fig. 1H and I). Collectively, PRDX1 knockdown restrains DLBCL cell proliferation, migration, and invasion, and promotes apoptosis.

Fig. 1
figure 1

Knockdown of PRDX1 inhibits DLBCL cell proliferation, migration, and invasion, while enhancing apoptosis. A. PRDX1 expression was analyzed in patients with DLBCL in the GEPIA2 database. The red box represents tumor samples, and the blue box represents normal samples. B. Using the GSE95290 dataset from the Oncomine database, PRDX1 expression was detected in DLBCL tissues. The scatter plot shows PRDX1 expression in each sample, with red dots representing cancer samples and blue dots representing normal samples. C. PRDX1 expression in DLBCL cell lines (OCI-Ly3 and DB) was quantified by RT-qPCR. *P < 0.05, **P < 0.01 vs. normal or GM12878 group. D-E. Transfection efficiency was confirmed by RT-qPCR and western blot following siRNA transfection. F. Using the CCK-8 assay, growth curves were generated based on OD450 after PRDX1 knockdown. G. Flow cytometry analysis with Annexin V-FITC and PI staining was used to determine the cell apoptosis level after PRDX1 knockdown. H-I. The evaluation of cell migration and invasion following PRDX1 knockdown was conducted via the Transwell assays. **P < 0.01 vs. si-NC group

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PRDX1 knockdown promotes erastin-induced ferroptosis in DLBCL cells

We then explored the effect of PRDX1 on erastin-induced ferroptosis. Erastin treatment downregulated PRDX1 protein levels in OCI-Ly3 and DB cells (Fig. 2A). Cell viability assays were then performed in PRDX1-knockdown and control cells treated with or without erastin. CCK-8 results indicated that in the DMSO-treated group, PRDX1 knockdown did not significantly affect cell viability in either OCI-Ly3 or DB cells. However, in the erastin-treated group, PRDX1 silencing significantly reduced cell viability, suggesting that PRDX1 depletion sensitized DLBCL cells to ferroptosis (Fig. 2B). The levels of ferroptosis markers in DLBCL cells were then quantified. In the DMSO-treated group, PRDX1 knockdown had no significant effect on MDA, iron, and GSH levels. Upon erastin treatment, PRDX1 knockdown increased MDA and iron levels while reducing GSH levels (Fig. 2C). Moreover, western blot analysis showed that PRDX1 silencing increased COX2 expression while reducing GPX4 expression under erastin-induced conditions, an effect not observed in the DMSO-treated group (Fig. 2D). These data suggest that PRDX1 knockdown can enhance DLBCL cell sensitivity to erastin-induced ferroptosis.

Fig. 2
figure 2

PRDX1 knockdown facilitates erastin-induced ferroptosis in DLBCL cells. (A) Western blot analysis was performed to assess PRDX1 protein expression in OCI-Ly3 and DB cells treated with or without erastin. (B) Cell viability was measured by CCK-8 assay in OCI-Ly3 and DB cells transfected with si-NC (negative control siRNA) or si-PRDX1 and treated with or without erastin. (C) Lipid peroxidation and ferroptosis-related markers, including MDA levels, intracellular iron levels, and GSH content, were measured in OCI-Ly3 and DB cells transfected with si-NC or si-PRDX1, with or without erastin treatment. (D) Protein levels of ferroptosis-related markers, including COX2 and GPX4 were quantified by western blot in OCI-Ly3 and DB cells transfected with si-NC or si-PRDX1 and treated with or without erastin. *P < 0.05, **P < 0.01 vs. DMSO group or si-NC (erastin) group

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Fig. 3
figure 3

Transcriptome sequencing was used to explore the target of PRDX1 in DLBCL. A. A Volcano plot of significantly up- and down-regulated genes after PRDX1 knockdown. The screening criteria for differentially expressed genes (DEGs) were based on the|log2 FC| > 1 and P < 0.05. B. A heat map of DEGs between the si-NC and si-PRDX1 groups. C. The bubble chart of Gene Ontology (GO) annotation. D. The bubble chart of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways

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DEGs identification by transcriptome sequencing and functional enrichment analysis

Three OCI-Ly3 cell samples from the si-NC and si-PRDX1 groups were subjected to transcriptome sequencing, respectively. The sequencing results showed a total of 116 DEGs between the si-NC and si-PRDX1 groups. Of these, 50 genes exhibited significant up-regulation, while 66 genes showed significant down-regulation. DEGs were visualized by the volcano and heat map (Fig. 3A and B). Additionally, the top 15 genes with upregulated and downregulated expression are presented in Supplementary Table 2. To investigate the possible biological roles of PRDX1-associated DEGs, GO annotation and KEGG functional enrichment analyses were performed. For GO annotation, DEGs were mainly enriched in response to organic substance, type 2 fibroblast growth factor receptor binding, and extracellular region (Fig. 3C). KEGG enrichment analysis revealed that DEGs were primarily engaged in the human papillomavirus infection, pathways in cancer, and the MAPK signaling pathway (Fig. 3D).

PRDX1 knockdown promotes erastin-induced ferroptosis in DLBCL cells by inhibiting the MAPK/ERK pathway

To investigate whether PRDX1 modulates the MEK/ERK pathway, we performed western blot analysis to examine the phosphorylation levels of ERK and MEK. The results revealed that erastin treatment significantly decreased the p-ERK and p-MEK levels in both OCI-Ly3 and DB cells compared to DMSO-treated controls, and these trends were further enhanced by the PRDX1 knockdown. When MEK/ERK pathway activator anisomycin was introduced, the PRDX1 knockdown and erastin-induced decrease in p-ERK and p-MEK levels were partially abrogated (Fig. 4A). In the absence of erastin treatment, PRDX1 knockdown alone also significantly reduced p-ERK and p-MEK levels in OCI-Ly3 and DB cells (Fig. 4B). Furthermore, BVD-523, a specific MEK inhibitor, significantly reduced PRDX1 mRNA level in DLBCL cells (Fig. 4C). Subsequently, we assessed whether PRDX1 regulates erastin-induced ferroptosis via the MAPK/ERK pathway. CCK-8 results indicated a reduction in cell viability after erastin exposure, which was exacerbated by PRDX1 knockdown. This decline was significantly mitigated upon anisomycin treatment (Fig. 4D). Erastin facilitated iron accumulation and MDA levels while lowering GSH, and these effects were further amplified when PRDX1 knockdown. Anisomycin incorporation significantly attenuated the promotional effect of PRDX1 knockdown on iron and MDA levels as well as the inhibitory effect on GSH (Fig. 4E). The increase in COX2 and reduction in GPX4 protein levels induced by erastin were enhanced by PRDX1 knockdown, while anisomycin treatment counteracted PRDX1-mediated effects (Fig. 4F). These outcomes propose that PRDX1 knockdown may promote ferroptosis in DLBCL cells by inhibiting the MAPK/ERK pathway.

Fig. 4
figure 4

PRDX1 knockdown enhances erastin-induced ferroptosis in DLBCL cells through modulation of the MAPK/ERK pathway. A. Western blot analysis of p-ERK, total ERK, p-MEK, and total MEK protein expression in OCI-Ly3 and DB cells transfected with si-NC or si-PRDX1, and treated with DMSO, erastin, or MAPK/ERK pathway anisomycin treatment. B. Western blot analysis of p-ERK, total ERK, p-MEK, and total MEK protein expression in OCI-Ly3 and DB cells after PRDX1 knockdown only under DMSO treatment conditions. C. RT-qPCR analysis of PRDX1 expression in DLBCL cells treated with the MAPK/ERK pathway inhibitor (BVD-523). D. The viability of DLBCL cells following PRDX1 knockdown, erastin, DMSO, or anisomycin treatment was assessed using CCK-8 assay. E. The assessment of ferroptosis-related indicators, including MDA, iron, and GSH, was performed after the PRDX1 knockdown and treatment with erastin, DMSO, or anisomycin. F. Protein levels of COX2 and GPX4 were measured by western blot following PRDX1 knockdown, erastin, DMSO, or anisomycin treatment. **P < 0.01 vs. DMSO or si-NC (DMSO) group; ##P < 0.01 vs. si-NC (erastin) group; &P < 0.05, &&P < 0.01 vs. si-PRDX1 (erastin) group

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PRDX1 knockdown hinders DLBCL cell proliferation, migration, and invasion and promotes apoptosis by inhibiting the MAPK/ERK pathway

DLBCL cell lines with PRDX1 knockdown were then treated with the MAPK/ERK pathway agonist anisomycin. We found that DLBCL cell proliferation was elevated in the si-PRDX1 + anisomycin group in relation to the si-PRDX1 group (Fig. 5A). Anisomycin treatment considerably attenuated PRDX1 knockdown-induced apoptosis in OCI-Ly3 and DB cells (Fig. 5B). Furthermore, PRDX1 knockdown suppressed DLBCL cell migration and invasion, while anisomycin treatment significantly reversed these trends (Fig. 5C and D). Therefore, we suggest that silencing PRDX1 impairs malignant phenotypes of DLBCL cells by blocking the MAPK/ERK pathway.

Fig. 5
figure 5

PRDX1 knockdown impedes the DLBCL cell malignant behaviors by suppressing the MAPK/ERK pathway. A. The proliferation of cells was measured with the CCK-8 method after PRDX1 knockdown and anisomycin treatment. B. Cell apoptosis was detected using flow cytometry after the knockdown of PRDX1 and anisomycin treatment. C-D. Cell migration and invasion was assessed using the Transwell assays following PRDX1 knockdown and treatment with anisomycin. **P < 0.01 vs. si-NC group; ##P < 0.01 vs. si-PRDX1 group

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PRDX1 knockdown inhibits DLBCL xenograft tumor growth by inhibiting the MAPK/ERK pathway

We constructed OCI-Ly3 xenograft models to explore the role of PRDX1 in vivo. In the lv-PRDX1 group, tumor sizes were diminished compared to the lv-NC group (Fig. 6A). Tumor weight and volume of mice in the lv-PRDX1 group were reduced relative to the lv-NC group (Fig. 6B). IHC staining was used to measure GPX4 and ki67 expression levels in the tumor tissues of mice and findings indicated a marked decrease in GPX4 and ki67-positive cells in the lv-PRDX1 group in contrast to the lv-NC group (Fig. 6C and D). Moreover, we also observed reduced expression levels of ferroptosis-associated proteins GPX4 and SCL7A11 in mouse tumor tissues after PRDX1 knockdown (Fig. 6E). In addition, PRDX1 knockdown decreased p-ERK/ERK level (Fig. 6F). The above findings suggest that PRDX1 knockdown inhibits the growth of DLBCL xenograft tumors and hinders the MAPK/ERK pathway.

Fig. 6
figure 6

PRDX1 knockdown inhibits DLBCL xenograft tumor growth. A. Tumor formation in mice injected with OCI-Ly3 cells stably transduced with the lv-PRDX1 or lv-NC vectors was observed (n = 6). B. Tumor weight change and tumor growth curve after PRDX1 Knockdown. C-D. The immunohistochemistry assay was conducted to measure the expression of GPX4 (Magnification: 400×, Scale: 100 μm) and ki67 (Magnification: 400×, Scale: 100 μm) in tumor samples in the lv-NC group and lv-PRDX1 group. E. The protein expression levels of GPX4 and SCL7A11 in DLBCL cells were measured using western blot. F. Western blot analysis was conducted to measure the protein levels of p-ERK and ERK. **P < 0.01 vs. lv-NC group

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Discussion

In recent years, research has increasingly focused on using ferroptosis induction as a strategy to bypass apoptosis resistance, offering a potential treatment for tumors resistant to conventional therapies [24]. Nonetheless, tumor cells can evade ferroptosis through various mechanisms that contribute to tumor expansion; thus, a deeper understanding of the molecular mechanisms of ferroptosis is critical for designing more effective targeted therapies [25, 26]. Our research indicated that PRDX1 expression was increased in DLBCL. Knockdown of PRDX1 decreased proliferation, migration, and invasion of OCI-Ly3 and DB cells, and promoted apoptosis and erastin-induced ferroptosis by inhibiting the MAPK/ERK pathway. In addition, PRDX1 knockdown impeded xenograft tumor growth in DLBCL.

PRDX1 functions dually as both a peroxidase and a molecular chaperone. It has been recognized as a dual regulator of tumorigenesis. In nasopharyngeal cancer tissues, PRDX1 expression is downregulated, and PRDX1 overexpression inhibits nasopharyngeal cancer cell metastasis and tumor growth by inhibiting the PI3K/AKT/TRAF1 pathway activation [27]. However, PRDX1 facilitates cilia disassembly and primary cilia loss, reinforcing the invasiveness of esophageal squamous cell carcinoma [28, 29]. A previous study has shown that PRDX1 expression is elevated in NHL cells [13]. This investigation demonstrated that PRDX1 was highly expressed in OCI-Ly3 and DB cells. PRDX1 played a crucial role in regulating DLBCL progression by modulating tumor cell viability, invasiveness, and ferroptosis susceptibility. In vivo findings further confirmed its knockdown inhibited xenograft tumor growth, highlighting its potential as a therapeutic target for DLBCL. Furthermore, PRDX1 inhibitors exhibit antitumor activity in tumors, such as urea derivatives of celastrol [30] and natural piericidins [31]. Thus, inhibiting PRDX1 expression could be a promising approach for DLBCL treatment.

Apoptosis resistance presents significant challenges in tumor therapy as it enables cancer cells to evade treatment-induced cell death, leading to tumor persistence and progression [32]. Previous studies have shown that PRDX1 silencing induces tumor apoptosis [33, 34]. The current study further demonstrated that PRDX1 knockdown promoted apoptosis levels in DLBCL cells. Ferroptosis is a novel type of non-apoptotic cell death and defined by excess iron, lipid peroxidation, and ROS accumulation. It is emerging as a potential treatment method for anti-apoptosis resistance in tumors [35]. Erastin is a widely studied ferroptosis inducer that selectively targets system Xc⁻, depleting intracellular GSH and leading to lipid peroxidation and ferroptotic cell death [36]. Erastin can trigger multiple pathways to rapidly and effectively inhibit tumor growth [37, 38]. It has been shown to enhance the sensitivity of many cancer cells to various chemotherapeutic agents and increase their sensitivity to radiation therapy [39]. However, current research on erastin remains insufficient, and further studies are needed to elucidate its specific mechanisms and optimize its therapeutic application. In this study, we found that under erastin treatment, PRDX1 deletion markedly increased iron and MDA levels, as well as COX2 protein expression, while leading to a decline in GSH levels and GPX4 and SCL7A11 protein expressions in DLBCL. PRDX1 is an antioxidant enzyme that scavenges excess hydrogen peroxide and organic peroxides to maintain redox homeostasis [40]. In addition to its peroxidase activity, PRDX1 functions as a molecular chaperone and stabilizes the transcription factor NRF2, which in turn maintains the expression of downstream antioxidant GPX4 and SLC7A11 and prevents the accumulation of lipid peroxides [41]. These findings suggest that PRDX1 exerts an inhibitory effect on ferroptosis in tumors. As a key component of the system Xc⁻ antiporter, SLC7A11 is instrumental in mediating cystine uptake and contributes to GSH synthesis [42]. GPX4 is a key regulator of ferroptosis, responsible for reducing lipid peroxides on the cell membrane and protecting cells from oxidative damage. Its activity depends on GSH as a reducing agent; therefore, once GPX4 or GSH is depleted, lipid peroxides on the cell membrane will accumulate uncontrollably and subsequently trigger ferroptosis [43, 44]. Unlike GPX4, COX2 is an upregulated response molecule during ferroptosis, and its inflammatory metabolic products may create a positive feedback loop that exacerbates oxidative damage and lipid peroxidation [45, 46]. These findings indicate that PRDX1 may function as a key suppressor of erastin-induced ferroptosis by regulating oxidative stress, lipid peroxidation, and inflammatory responses in DLBCL cells. Additionally, interference with PRDX1, particularly through LncFASA-mediated liquid-liquid phase separation, leads to excessive lipid peroxidation and enhances breast cancer cell vulnerability to ferroptosis [47]. PRDX1 knockdown also promotes ferroptosis in colorectal cancer and prostate cancer [41, 48]. Hence, PRDX1 inhibition may sensitize tumor cells to ferroptosis, contributing to improved therapeutic efficacy in cancer.

The MAPK pathway is an intracellular signaling cascade that regulates numerous cellular processes, such as growth, proliferation, migration, and apoptosis. The MAPK cascade involves a series of phosphorylation events: MAPKKK (Raf) phosphorylates MAPKK (MEK), which subsequently activates MAPK (ERK) [49]. The expression and activation of MAPK are significantly associated with a poor response to CHOP treatment in patients with DLBCL [50]. Despite extensive efforts to develop effective MAPK/ERK pathway inhibitors like vemurafenib [51] and dabrafenib [52] for clinical use, reactivation of ERK signaling can lead to resistance to RAF or MEK inhibitors [53]. Ferroptosis is closely associated with stress-activated signaling pathways, particularly the MAPK pathway [54]. Key MAPK components, such as ERK, JNK, and p38 MAPK, are involved in the regulation of iron metabolism and oxidative stress-related factor levels [55]. The MAPK signaling pathway has a dual role in the regulation of tumor ferroptosis. Increased phosphorylation of JNK, p38, and ERK contributes to ferroptosis in various tumors, such as pancreatic cancer, colon cancer, and osteosarcoma by enhancing ROS production, reducing GPX4 and SCL771 expressions, increasing intracellular iron levels, and regulating autophagy [56, 57]. Notably, persistent activation of ERK1/2 kinases promotes cell proliferation and aggressiveness [58, 59], while inhibition of this pathway may reduce cellular stress resistance, potentially enhancing ferroptosis induction. It is reported that heteronemin, a marine natural product isolated from Hippospongia sp, induces ferroptosis while simultaneously reducing ERK expression levels in hepatocellular carcinoma cells [60]. Meng et al. found that MSI2, an RNA-binding protein, suppress the p-ERK/p38/MAPK axis, thereby inhibiting the phosphorylation of MAPKAPK2 and HSPB1, reducing the expression of proliferation markers PCNA and ki67 in cancer cells, and ultimately facilitating ferroptosis [61]. Additionally, chemotherapy-activated MAPK signaling stimulates ERK phosphorylation of the RFNG Ser255 residue and inhibits p53 axis, leading to the suppression of both apoptosis and ferroptosis. This effect significantly enhances cancer cell resistance to oxaliplatin treatment in colorectal cancer [62]. Therefore, targeting MAPK/ERK may be a promising strategy for enhancing ferroptosis-based cancer therapy. Importantly, it is reported that PRDX1 is closely associated with the MAPK/ERK pathway. In Ras-driven liver cancer models, PRDX1 has been found to positively regulate the Ras/ERK/FoxM1 axis and stimulate NRF2 activity, inhibiting oxidative damage and promoting tumor cell survival [63]. In our study, IHC staining also revealed that PRDX1 knockdown reduced the expression of ki67, a monitoring marker of tumor proliferative activity. Therefore, PRDX1 knockdown may impair weaken ERK-mediated pro-growth signaling, ultimately increasing cellular vulnerability to ferroptosis.

Our study demonstrated that PRDX1 knockdown enhanced ferroptosis and inhibited the growth of DLBCL, highlighting its potential as a therapeutic target. However, several challenges must be addressed before clinical application. First, given the critical role of PRDX1 in maintaining redox homeostasis in normal tissues, its systemic inhibition may lead to adverse effects, including oxidative stress-related damage to non-cancerous cells [64, 65]. Studies have shown that PRDX1 is essential for protecting red blood cells and cardiomyocytes from oxidative damage, and its inhibition could increase the risk of hemolysis or cardiotoxicity [66, 67]. Additionally, excessive ferroptosis induction may pose a risk to neuronal cells, potentially leading to neurotoxicity [68]. To mitigate these potential side effects, tumor-specific delivery mechanisms should be elucidated, such as nanoparticle-based drug carriers or antibody-drug conjugates, to selectively inhibit PRDX1 in DLBCL cells while minimizing systemic toxicity. Furthermore, not all patients will respond to ferroptosis-based therapies due to the heterogeneity of DLBCL [69]. Transcriptomic and proteomic analyses to identify biomarkers should be further performed to predict ferroptosis sensitivity in DLBCL patients. Lastly, the limitations of current DLBCL animal models need to be addressed. Traditional xenograft models may inadequately mimic the intricate interactions within the tumor microenvironment. Therefore, we will establish patient-derived organoid and patient-derived xenograft models to further evaluate the correlation between PRDX1 and NRF2, as well as whether the combination of PRDX1 inhibitors with ferroptosis inducer erastin and MAPK inhibitors enhances the therapeutic effect in DLBCL in the following study.

Conclusion

This study demonstrates that PRDX1 expression is elevated in DLBCL. Knockdown of PRDX1 inhibits human DLBCL cell proliferation, metastasis, and xenograft tumor growth. Moreover, PRDX1 knockdown enhances erastin-induced ferroptosis. The MAPK/ERK pathway is mediated by PRDX1. PRDX1 knockdown decreases p-ERK/ERK level, which further inhibits DLBCL cell malignant phenotypes. This study provides a new insight to develop a promising strategy for DLBCL.

Data availability

All data can be obtained by contacting the corresponding author.

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Funding

General Project of Natural Science Foundation of Jiangxi Provincial Department of Science and Technology (No. 20232BAB206059).

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Authors and Affiliations

  1. Department of Hematology, First Affiliated Hospital of Gannan Medical University, No. 128, Jinling Road, Economic Development District, Ganzhou City, Jiangxi Province, 341000, China

    Chuanming Lin & Shuiling Xie

  2. Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou City, Fujian Province, 350001, China

    Chuanming Lin & Jianzhen Shen

  3. Gannan Medical University, Rongjiang New District University Park, Ganzhou City, Jiangxi Province, 341099, China

    Menger Wang

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Chuanming Lin: Conception and design of the research, Acquisition of data, revision of manuscript for important intellectual content; Menger Wang and Jianzhen Shen: Acquisition of data, performing the experiment, drafting the manuscript; Shuiling Xie: Analysis and interpretation of data; performing the experiment.All the authors read and approvaled the manuscript.

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Supplementary Material 1: Gene set enrichment analysis (GSEA) based on the GSE95290 dataset. The x-axis represents the rank in the ordered dataset, with genes ranked from most to least correlated with the phenotype. The y-axis shows the running enrichment score, which reflects the cumulative enrichment of the gene set as it moves down the ranked list.

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Lin, C., Xie, S., Wang, M. et al. PRDX1 knockdown promotes erastin-induced ferroptosis and impedes diffuse large B-cell lymphoma development by inhibiting the MAPK/ERK pathway. BMC Cancer 25, 806 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14173-1

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