In the relentless quest to conquer acute myeloid leukemia (AML), a formidable adversary within the realm of hematologic malignancies, scientific attention has recently converged on the transcription factor Nrf2. Known formally as nuclear factor erythroid 2–related factor 2, this protein has emerged as a pivotal driver in the dynamic interplay of chemoresistance mechanisms that thwart therapeutic success in AML. This new review by Mathew and Gopalakrishnan, published in Medical Oncology, untangles the complexities of Nrf2’s regulatory network and spotlights innovative strategies aiming to dismantle its protective shield in leukemia cells. What unfolds is an intricate portrait of molecular resilience, where the cancer’s survival tactics hinge on a biochemical guardian long underestimated by oncologists.
Nrf2’s primary physiological role is to serve as a master regulator of cellular antioxidant responses, orchestrating the expression of myriad cytoprotective genes that neutralize oxidative stress and maintain redox homeostasis. In healthy cells, this function acts as a frontline defense against environmental toxins and metabolic byproducts. However, within the malignant environment of AML, this protective program becomes hijacked to foster survival despite the cytotoxic challenge posed by chemotherapy. The review delineates how persistent activation of Nrf2 in leukemic blasts underlies a spectrum of adaptive responses, granting these cells an elevated threshold against therapeutic agents designed to induce oxidative damage and apoptosis.
This aberrant activation of Nrf2 unfolds primarily through disruption of its negative regulatory axis involving KEAP1 (Kelch-like ECH-associated protein 1). Normally, KEAP1 binds Nrf2 under basal conditions, tagging it for proteasomal degradation. Mutations, epigenetic alterations, or oxidative modifications can impair KEAP1 function, leading to sustained nuclear accumulation of Nrf2 and constitutive transcriptional activation of detoxification pathways. Mathew and Gopalakrishnan’s review further elucidates how such molecular perturbations create a resistant leukemic phenotype, impervious to standard chemotherapeutic regimens such as cytarabine and anthracyclines.
Central to Nrf2’s oncogenic resilience is its governance over a battery of genes encoding for antioxidants, phase II detoxification enzymes, and drug efflux transporters. These include glutathione-S-transferases, NAD(P)H quinone dehydrogenase 1 (NQO1), and multidrug resistance proteins. By upregulating these defensive armaments, AML cells not only neutralize reactive oxygen species but also actively expel chemotherapeutic compounds, reducing intracellular drug accumulation. The review underscores that this concerted molecular armor formation dramatically diminishes treatment efficacy and is a primary reason for relapse and poor patient prognosis.
The mechanistic insights provided by this updated review offer a roadmap for targeting Nrf2 therapeutically. Direct inhibition of Nrf2 remains challenging due to its nature as a transcription factor, but indirect strategies—such as restoring KEAP1 function or modulating upstream signaling cascades—are under intense investigation. Small molecules that reactivate KEAP1-mediated degradation of Nrf2 or disrupt Nrf2-DNA binding have emerged as enticing candidates. In parallel, targeting downstream effectors within the Nrf2 pathway presents alternative angles to undermine the leukemia cell’s defensive bulwark.
Intriguingly, Nrf2 also influences metabolic reprogramming in AML cells. The review highlights how activation of this pathway promotes shifts in glucose and glutamine metabolism that fuel cellular biosynthesis and redox balance, effectively supporting the high proliferative demands of leukemic cells. This metabolic plasticity encourages survival in hostile microenvironments and further complicates therapeutic intervention. Novel metabolic inhibitors combined with Nrf2 modulators may therefore offer synergistic potential, a frontier the review advocates for rigorous exploration.
Importantly, Mathew and Gopalakrishnan caution that Nrf2’s role is not merely black and white. While predominantly a facilitator of chemoresistance in AML, Nrf2 also exerts context-dependent functions that may influence immune cell interactions and inflammatory signaling within the bone marrow niche. These nuanced effects necessitate careful calibration of any Nrf2-targeted therapies to avoid systemic toxicities or unintended immune suppression. The review calls for more comprehensive analyses of Nrf2’s crosstalk with the tumor microenvironment to develop refined therapeutic windows.
Preclinical models have provided promising proof-of-concept for Nrf2 pathway inhibition. Using AML cell lines and xenograft mouse models, several studies summarized in the review demonstrate restored sensitivity to chemotherapeutics upon pharmacologic attenuation of Nrf2 signaling. However, translating these findings into clinical benefit remains an ongoing challenge. The authors emphasize a need for biomarker development to identify patients most likely to benefit from Nrf2-targeted interventions, aligning with the broader trend of precision oncology.
The dynamic role of Nrf2 extends beyond AML into other hematologic cancers and even solid tumors, underscoring its universal importance in cancer biology. However, its particularly insidious influence in AML derives from the disease’s acute nature and the limited therapeutic options once resistance emerges. This review situates Nrf2 as a linchpin in the molecular architecture of therapy failure and proposes that a paradigm shift in targeting this pathway could redefine AML treatment outcomes.
Excitingly, the review highlights emerging synergistic therapeutic combinations. Pairing Nrf2 inhibition with agents that induce oxidative stress or DNA damage creates a synthetic lethality environment, overwhelming leukemic defenses. Moreover, combination therapies employing immunomodulators to harness anti-tumor immunity alongside Nrf2 pathway disruption suggest multidisciplinary strategies on the horizon. These integrative approaches may not only improve remission rates but also prevent or delay resistance development.
Beyond pharmacological approaches, the review touches on the potential of gene editing techniques, such as CRISPR-Cas9, to precisely modulate Nrf2 or KEAP1 genes in leukemic stem cell populations. These technologies, though nascent, promise long-term suppression of chemoresistance and hold potential for curative interventions. Ethical and safety considerations remain paramount, but the conceptual leap toward molecular reprogramming of leukemic resilience is compelling.
Furthermore, the elucidation of Nrf2’s role enriches our broader understanding of cancer stem cell biology. AML stem cells exploit Nrf2-driven pathways to maintain a redox environment conducive to quiescence and survival, effectively evading many conventional treatments that target cycling cells. Thus, overcoming Nrf2-mediated chemoresistance aligns with targeting stemness properties essential for durable leukemia eradication.
In conclusion, this comprehensive review by Mathew and Gopalakrishnan crystallizes the evolving scientific consensus: Nrf2 is both a guardian of cellular health and an accomplice in oncologic defiance. The dualistic nature of this transcription factor demands precision in therapeutic targeting to avoid collateral damage. Yet, the promise of effective Nrf2 modulation in enhancing AML treatment paradigms is palpable. As research accelerates, targeting Nrf2 is poised to become a cornerstone in the next generation of leukemia therapies, potentially transforming a once grim prognosis into a triumph of molecular medicine.
Subject of Research: Acute Myeloid Leukemia and the role of Nrf2 in chemoresistance
Article Title: Targeting Nrf2 in acute myeloid leukemia: an updated review on its role in chemoresistance and emerging therapeutic strategies
Article References:
Mathew, D.M., Gopalakrishnan, A.V. Targeting Nrf2 in acute myeloid leukemia: an updated review on its role in chemoresistance and emerging therapeutic strategies. Med Oncol 42, 460 (2025). https://doi.org/10.1007/s12032-025-03012-9
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