Zileuton Beyond Asthma: A Multifaceted 5-Lipoxygenase Inhibitor With Emerging Therapeutic Potential Across Inflammation, Cancer, Neuroprotection, and Fibrosis.

Authors

Victor D Ivancev, Joshua Iskander, Julia Hanna, Kiran Ghotra, Clark Iorio, Diana V Ivancev

Published in

Cureus. Volume 18. Issue 9. Pages e116354. Epub Sep 16, 2026.

Abstract

Zileuton is a selective, orally active inhibitor of the enzyme 5-lipoxygenase (5-LOX), originally developed and clinically approved for the prophylaxis and chronic management of asthma. Discovered in the 1980s, its unique pharmacological mechanism distinguishes it from other widely used leukotriene receptor antagonists. Rather than blocking downstream receptors, zileuton acts upstream to suppress the overall synthesis of all 5-LOX-derived eicosanoids. It achieves this by directly inhibiting the conversion of arachidonic acid into leukotriene A4 (LTA₄), thereby halting the subsequent production of both the potent chemoattractant leukotriene B4 (LTB₄) and the cysteinyl leukotrienes responsible for bronchoconstriction and airway inflammation. Although its formally approved therapeutic identity has remained largely confined to asthmatic populations, emerging pathophysiological insights demonstrate that 5-LOX-derived lipid mediators participate in a substantially broader array of fundamental biological processes. Beyond mediating reactive airway disease, these leukotrienes and related lipid signaling molecules are critical drivers of leukocyte recruitment, vascular permeability, and systemic oxidative stress. Furthermore, 5-LOX activity has been increasingly implicated in complex cellular dynamics, including tumor-microenvironment interactions, tissue fibrosis, and the cascades of lipid peroxidation. These diverse physiological roles have prompted widespread translational investigation of zileuton in a variety of acute and chronic diseases that are substantially removed from its original clinical indication within the scope of pulmonology. To date, clinical studies have evaluated the therapeutic efficacy of 5-LOX inhibition in several inflammatory conditions, including chronic obstructive pulmonary disease (COPD), ulcerative colitis, rheumatoid arthritis, Sjögren-Larsson syndrome, atopic dermatitis, and acne, as well as in the chemoprevention of pulmonary carcinogenesis. Concurrently, a robust and expanding preclinical literature suggests significant potential for zileuton activity across an even wider spectrum of pathologies. This includes promising experimental efficacy against colorectal malignancy. Additionally, models have highlighted its neuroprotective potential in ischemic and traumatic neurologic injury and ferroptosis-associated neuronal damage. Systemic organ protection has also been observed in models of hepatic fibrosis, ischemic kidney injury, and drug-associated nephrotoxicity. By synthesizing these diverse findings, this review examines the underlying pharmacologic basis and the emerging translational evidence supporting the therapeutic repurposing of zileuton well beyond its traditional role in asthma.

PMID:
42891486
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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