BTK inhibitors work by suppressing Bruton’s tyrosine kinase, an enzyme that transmits signals essential for the growth, survival and activation of B cells. Because mantle cell lymphoma and several other B-cell malignancies depend heavily on these signaling pathways, drugs that inhibit BTK can produce powerful clinical responses. Yet the benefit is often temporary. Many patients relapse after one or two years as lymphoma cells acquire or select for biological changes that allow them to survive despite continued treatment.

The new study, published in Nature Communications, identifies an unexpected mechanism behind this resistance. In mantle cell lymphoma cells that remain sensitive to BTK inhibitors, treatment triggers ferroptosis rather than simply starving the cells of growth signals. Ferroptosis is a distinct form of regulated cell death driven by the uncontrolled oxidation of lipids, the fatty molecules that form cellular membranes. As oxidized lipids accumulate, the membrane loses its integrity and eventually ruptures, killing the cell.

This process depends on the presence of both reactive oxygen species and available iron. Iron can catalyze chemical reactions that convert relatively stable oxygen-containing molecules into highly reactive compounds. These reactions initiate a chain reaction in membrane lipids, producing toxic lipid peroxides. Healthy cells normally prevent this damage through antioxidant systems, but rapidly dividing cancer cells operate under substantial metabolic stress and can become especially vulnerable when those defenses are disrupted.

Dr. Soo-Yeon Hwang, a postdoctoral associate in the laboratory of Dr. Jihye Paik at Weill Cornell Medicine, and colleagues compared lymphoma cells obtained from patients who responded to BTK inhibitors with cells from patients whose cancers had become resistant. The distinction was striking. BTK treatment induced the molecular and biochemical features of ferroptosis in sensitive cells, while resistant cells avoided the same fate. The researchers traced this difference to abnormal activity of BRG1, a protein that regulates how DNA is packaged and read.

BRG1 is a chromatin remodeler, meaning that it helps rearrange the structure of chromatin—the complex of DNA and proteins inside the nucleus. By repositioning nucleosomes, the compact units around which DNA is wrapped, chromatin remodelers can make particular genes more or less accessible to the transcriptional machinery. This gives them broad influence over cellular behavior. In mantle cell lymphoma, BRG1 is frequently mutated or otherwise dysregulated in tumors that no longer respond to BTK inhibitors.

The researchers found that aberrant BRG1 rewires gene expression in a way that suppresses ferroptosis. Its activity reduces the cellular conditions required for the death process, including the accumulation of reactive oxygen and free iron. In effect, BRG1 acts as a protective shield: while BTK inhibition places the lymphoma cell under stress, BRG1 strengthens the cell’s ability to neutralize oxidative damage before it can spread through the membrane.

This finding helps explain why simply continuing BTK inhibitor treatment may fail even when the drug remains capable of blocking its original molecular target. Resistance does not necessarily arise because the lymphoma cell restores BTK signaling. Instead, the cell can bypass the lethal consequences of BTK inhibition by changing its metabolism and antioxidant defenses. BRG1 therefore represents a vulnerability downstream of the drug’s primary target, one that may be exploitable even after the cancer has stopped responding to BTK therapy.

In laboratory experiments and animal models, combining a BRG1 inhibitor with a BTK inhibitor substantially increased antitumor activity compared with BTK inhibition alone. The combination also extended survival in treated animals. These results provide early evidence for a therapeutic strategy in which the cancer’s antioxidant protection is dismantled while BTK signaling is simultaneously suppressed. The approach could potentially be relevant beyond mantle cell lymphoma, although its safety and effectiveness in people will require clinical testing.

The study also highlights the growing importance of ferroptosis in cancer biology. Unlike apoptosis, the best-known form of programmed cell death, ferroptosis is governed by iron handling, lipid metabolism and cellular redox balance. Because malignant cells frequently divide rapidly and remodel their membranes at high rates, they may carry a biochemical weakness that can be exposed by targeted therapies. The Weill Cornell findings suggest that understanding which tumors retain or suppress this weakness could help guide treatment decisions and reveal combination therapies for patients whose cancers have become resistant.

Web References: https://www.nature.com/articles/s41467-026-75123-4

References: Nature Communications study published 2 July 2026; Weill Cornell Medicine investigators Dr. Soo-Yeon Hwang, Dr. Jihye Paik and Dr. Hongwu Zheng.

Keywords: Mantle cell lymphoma, BTK inhibitors, Bruton’s tyrosine kinase, BRG1, ferroptosis, oxidative stress, cancer drug resistance, B lymphocytes, chromatin remodeling, targeted therapy

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