PRDX1 Knockdown Triggers Ferroptosis, Halts Lymphoma

In a groundbreaking advancement in cancer research, scientists have uncovered a pivotal mechanism to combat diffuse large B-cell lymphoma (DLBCL), one of the most aggressive and common forms of lymphoma affecting adults worldwide. This study focuses on the role of peroxiredoxin 1 (PRDX1), an antioxidant enzyme, in modulating a specialized form of cell death known as ferroptosis, and reveals promising therapeutic avenues for treating this malignancy. Published in the latest issue of BMC Cancer, the research delineates how downregulation of PRDX1 not only enhances ferroptosis but also represses the MAPK/ERK signaling pathway, thereby curbing lymphoma progression.

Diffuse large B-cell lymphoma is notoriously challenging due to its rapid progression and resistance to conventional therapies. Targeting cellular vulnerabilities such as ferroptosis—a type of programmed cell death driven by iron-dependent lipid peroxidation—has emerged as a novel strategy. Previous attempts to induce ferroptosis faced obstacles in efficiently translating these mechanisms into clinical treatment, which underscores the importance of identifying molecular regulators like PRDX1.

PRDX1 serves critical cellular functions in maintaining redox homeostasis by detoxifying peroxides, thereby protecting cells against oxidative stress. Its role in cancer biology remains complex, often exhibiting dual characteristics; while it can protect normal cells by mitigating oxidative damage, it also aids cancer cell survival under stressful microenvironmental conditions. The current study provides compelling evidence that PRDX1 is upregulated in DLBCL—suggesting it acts as a cancer promoter by shielding malignant cells from ferroptotic death.

Utilizing a combination of bioinformatics and quantitative real-time PCR, the researchers quantified elevated PRDX1 expression in DLBCL tissues and cell lines relative to healthy counterparts. This overexpression correlates with enhanced proliferative and invasive capabilities, highlighting PRDX1’s potential as a therapeutic target. Subsequent in vitro experiments demonstrated that silencing PRDX1 expression adversely affects lymphoma cell viability by restricting proliferation, inhibiting migration and invasion, and promoting apoptotic pathways.

The authors then explored the interplay between PRDX1 and ferroptosis, using erastin, a small molecule known to induce ferroptosis specifically. Upon PRDX1 knockdown, lymphoma cells exhibited heightened sensitivity to erastin, evidenced by increased intracellular iron and malondialdehyde (MDA) levels—hallmarks of lipid peroxidation. Moreover, a concomitant decrease in glutathione (GSH) levels was observed, further corroborating the intensified ferroptotic process. This biochemical milieu not only amplifies ferroptosis but simultaneously suppresses vital protective proteins such as GPX4 and SLC7A11, which typically inhibit ferroptotic cell death.

A deeper mechanistic analysis uncovered that PRDX1 modulates the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, a crucial signaling cascade involved in cellular growth, differentiation, and survival. The study revealed that PRDX1 knockdown decreased the phosphorylation of MEK and ERK kinases, effectively dampening MAPK/ERK pathway activity. Such inhibition corresponds with diminished malignancy of DLBCL cells and enhanced ferroptosis.

Importantly, the role of MAPK/ERK signaling in this context was further validated using anisomycin, an agonist of the pathway. Treatment with anisomycin reversed the suppressive effects on proliferation and invasion induced by PRDX1 silencing, and concurrently mitigated the enhancement of ferroptosis. These findings pinpoint the MAPK/ERK pathway as a downstream effector mediating the oncogenic impact of PRDX1 in DLBCL, providing a targetable link between redox regulation and malignancy.

The in vivo relevance of these observations was substantiated through xenograft tumor models, where PRDX1 knockdown markedly suppressed tumor growth in mice. This compelling evidence positions PRDX1 as an indispensable promoter of DLBCL progression and a regulator of ferroptotic susceptibility. By destabilizing the balance between cellular antioxidants and iron-dependent oxidative damage, PRDX1 knockdown primes lymphoma cells for ferroptosis, thus opening avenues for combinatorial therapeutic approaches integrating ferroptosis inducers.

This study’s implications extend beyond DLBCL. The elucidated connection between PRDX1, ferroptosis, and the MAPK/ERK pathway may be relevant across various malignancies where oxidative stress and MAPK signaling are aberrant. Targeting such multifaceted mechanisms offers heightened specificity and efficacy, potentially overcoming resistance seen with monotherapies.

From a clinical perspective, PRDX1 emerges as a promising biomarker for disease aggressiveness and therapeutic responsiveness. Measuring PRDX1 levels could aid in stratifying patients most likely to benefit from ferroptosis-based treatments. Moreover, suppression of PRDX1 activity might synergize with existing chemotherapeutic and immunotherapeutic modalities to enhance outcomes.

The intersection of ferroptosis and oncogenic signaling illuminated in this investigation heralds a paradigm shift. Instead of solely focusing on inhibiting cancer growth, harnessing regulated cell death pathways like ferroptosis, in conjunction with modulating survival signals such as MAPK/ERK, presents a dual-hit strategy against resilient tumors. This approach is poised to revolutionize targeted cancer therapy, particularly for aggressive lymphomas lacking effective treatment options.

In summary, this landmark research deciphers how PRDX1 orchestrates the survival and ferroptotic vulnerability of DLBCL cells through MAPK/ERK pathway regulation. Reducing PRDX1 levels sensitizes lymphoma cells to ferroptosis induction by erastin, impairs tumorigenic behaviors, and halts disease progression in preclinical models. As the scientific community continues to unravel the complexities of redox biology in cancer, such insights pave the way for novel, efficacious therapeutics tailored to exploit tumor-specific metabolic vulnerabilities.

The prospect of integrating PRDX1-targeted strategies with ferroptosis-inducing agents and MAPK pathway modulators offers exciting translational potential. Future research will undoubtedly explore combination regimens, dosing schedules, and delivery mechanisms to optimize patient outcomes while minimizing off-target effects. Ultimately, this study exemplifies the power of molecular oncology in identifying weaknesses within cancer’s armor and transforming them into therapeutic triumphs.

Subject of Research: Diffuse large B-cell lymphoma (DLBCL) and the role of peroxiredoxin 1 (PRDX1) in ferroptosis and MAPK/ERK pathway regulation.

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

Article References:
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://doi.org/10.1186/s12885-025-14173-1

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14173-1

Tags: antioxidant enzyme role in cancercancer research advancementsdiffuse large B-cell lymphoma treatmentferroptosis in lymphomairon-dependent cell deathlymphoma progression inhibitionMAPK/ERK signaling pathwaymolecular regulators in canceroxidative stress regulationPRDX1 knockdownprogrammed cell death mechanismstherapeutic strategies for lymphoma