Page 206 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology FN3K–Nrf2 axis inhibition in breast cancer

1. Introduction adaptability in cancer cells by alleviating oxidative stress
and maintaining redox homeostasis, thereby underscoring
Breast cancer persists as a predominant contributor to its potential as an emerging therapeutic target in breast
global cancer-related mortality, with the efficacy of present cancer. FN3K modulates the activity of redox-sensitive
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therapeutic modalities often constrained by systemic transcription factors, such as Nrf2 by catalyzing the
toxicities and the progressive development of multidrug deglycation of essential lysine and arginine residues critical
resistance. Recent global statistics indicate that, in 2022, for transcriptional activation. Glycation of Nrf2 impairs
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breast cancer was diagnosed in approximately 2.3 million its stability, nuclear translocation, and interaction with
women worldwide, leading to more than 670,000 reported small musculoaponeurotic fibrosarcoma (sMAF) proteins,
deaths. Although incidence rates are higher in high-income thereby attenuating its antioxidant transcriptional
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countries, mortality remains disproportionately elevated in program. Conversely, FN3K overexpression maintains
low-resource settings due to delayed diagnosis and limited Nrf2 in a functional state, promoting redox homeostasis
access to effective treatment options. The complexity of and facilitating tumor cell survival under oxidative stress.
breast cancer, encompassing diverse molecular subtypes, Elevated FN3K activity has been associated with enhanced
presents significant therapeutic challenges. 1 Nrf2 signaling and poor prognosis in multiple cancer
Resistance to chemotherapeutic agents and targeted types, including breast cancer, underscoring its role in
therapies continues to undermine treatment efficacy, disease progression and therapy resistance. 5
underscoring the urgent need for novel therapeutic Using structure-based virtual screening (SBVS)
strategies. Emerging evidence underscores metabolic combined with molecular docking, Beeraka et al.
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reprogramming as a critical driver of cancer progression reported that multiple anti-cancer compounds – including
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and therapeutic resistance. To sustain uncontrolled tyrosine kinase inhibitors, hormonal modulators, and
growth and adapt to the tumor microenvironment, immunosuppressants – exhibited strong modulatory
cancer cells exhibit marked metabolic adaptability driven effects on FN3K activity. Beeraka et al. also identified
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by alterations in glycolysis, glutamine utilization, lipid several anti-cancer agents – including gefitinib, sorafenib,
processing, and mitochondrial respiration. Targeting neratinib, tamoxifen citrate, and cyclosporine A – as
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key metabolic enzymes within these reprogrammed potent modulators of FN3K through SBVS and molecular
pathways – such as hexokinase II, glutaminase, and fatty docking approaches. A separate study demonstrated
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acid synthase – has emerged as a promising therapeutic a strong positive correlation between FN3K levels and
strategy, offering selectivity by exploiting cancer-specific Nrf2-target antioxidant gene expression signatures,
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metabolic dependencies. However, the dynamic nature of implicating FN3K in sustaining redox homeostasis
metabolic adaptation highlights the need for combinatorial through Nrf2 pathway protection. Notably, elevated FN3K
approaches and robust biomarkers to improve therapeutic expression has been correlated with decreased disease-
efficacy. 2 specific survival, indicating its potential relevance as a
Fructosamine-3-kinase (FN3K) is a deglycating enzyme prognostic biomarker in breast cancer. Yousefi et al.
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that catalyzes the phosphorylation of fructosamine adducts conducted a comparative enzymatic analysis of FN3K
on glycated proteins, thereby promoting their elimination activity in paired breast tumor and adjacent normal
and aiding in protein quality control and repair. This tissues, revealing a significant reduction in FN3K activity
enzymatic activity plays a crucial role in mitigating cellular within tumor samples. This reduction may compromise
damage associated with non-enzymatic glycation, oxidative cellular deglycation efficiency, leading to the accumulation
stress, and metabolic dysregulation. A marked reduction of AGEs, which can disrupt protein function, elevate
in FN3K activity has been observed in breast cancer tissues oxidative stress, and facilitate malignant transformation
compared to adjacent normal tissues, indicating its potential by driving metabolic reprogramming. These observations
involvement in tumor progression and diminished defense highlight FN3K as a potential regulator of metabolic
against advanced glycation end products (AGEs). Beyond pathways involved in the pathogenesis of breast cancer.
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its role in protein repair through deglycation, FN3K has FN3K mediates a distinctive intracellular deglycation
been implicated in cancer progression by contributing to process by phosphorylating fructosamine adducts at the
the stabilization of nuclear factor erythroid 2-related factor third carbon of the deoxyfructose ring, thereby promoting
2 (Nrf2), a key transcription factor governing antioxidant their spontaneous breakdown and restoring free amino
defense mechanisms. This stabilization enhances groups. This enzymatic correction limits the formation of
Nrf2-mediated transcription of cytoprotective genes, stable AGEs, which are associated with persistent oxidative
thereby promoting cancer cell proliferation, survival, stress and inflammation – key pathophysiological factors
and resistance to therapy. FN3K facilitates metabolic in cancer initiation and progression. 8

Volume 9 Issue 3 (2025) 198 doi: 10.36922/EJMO025150114