Iron chelators reduce prostaglandins and leukotrienes by inhibiting cyclooxygenase and lipoxygenase: A hypothesis to attenuate PPARγ transcriptional activity in prostate cancer
Issued Date
2026-03-01
Resource Type
ISSN
03069877
eISSN
15322777
Scopus ID
2-s2.0-105029020087
Journal Title
Medical Hypotheses
Volume
208
Rights Holder(s)
SCOPUS
Bibliographic Citation
Medical Hypotheses Vol.208 (2026)
Suggested Citation
Noulsri E., Lerdwana S. Iron chelators reduce prostaglandins and leukotrienes by inhibiting cyclooxygenase and lipoxygenase: A hypothesis to attenuate PPARγ transcriptional activity in prostate cancer. Medical Hypotheses Vol.208 (2026). doi:10.1016/j.mehy.2026.111895 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/114888
Title
Iron chelators reduce prostaglandins and leukotrienes by inhibiting cyclooxygenase and lipoxygenase: A hypothesis to attenuate PPARγ transcriptional activity in prostate cancer
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Author's Affiliation
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Abstract
Aggressive prostate cancer (PC) relies on lipid metabolic reprogramming and pathological iron (Fe) accumulation to drive disease progression. While peroxisome proliferator-activated receptor-gamma (PPARγ) is a master regulator of this lipid-addicted phenotype, direct therapeutic targeting remains clinically limited by systemic toxicity. We propose a novel therapeutic framework: the Fe- cyclooxygenase (COX)/lipoxygenase (LOX)- prostaglandins (PGs)/leukotrienes (LTs)-PPARγ signaling axis. This hypothesis identifies intracellular iron bioavailability as the critical catalytic switch for oncogenic PPARγ activity. Within this axis, Fe serves as an essential cofactor for COX and LOX enzymes that synthesize activating eicosanoid ligands, PGs and LTs, required for receptor transactivation. This model shifts the paradigm of iron chelation from traditional nutritional starvation to a sophisticated signal-transduction interference strategy. By deactivating COX/LOX through active-site coordination and peroxide tone modulation, iron chelators e.g., deferoxamine, deferiprone induce a ligand deficit that forces PPARγ into an inactive apo-conformation, silencing pro-survival genes such as FASN and CD36. To validate this axis, we propose a multi-faced roadmap. This involves in vitro rescue experiments confirming that exogenous ligands bypass chelation-induced silencing, paired with in vivo transcriptomic RNA-seq and cistromic ChIP-seq mapping to verify the global attenuation of the PPARγ regulation. This signaling interference model provides a mechanistic rationale for using iron chelators as indirect transcriptional modulators. Such a strategy may provide a precision-guided approach for sensitizing castration-resistant disease to conventional therapeutic regimens.