Work

Natural bioactive compounds targeting the macrophage clock in asthma: evidence, challenges, and perspectives

Year: 2026

Type: review

Abstract: Background: Nocturnal asthma and airway remodeling are intimately linked to pulmonary circadian dysfunction. The dysregulation of core clock genes (e.g., Bmal1, Rev-erbα) in macrophages drives metabolic reprogramming and pro-fibrotic signaling. Pharmacological modulation of this clock using natural bioactive compounds offers a promising therapeutic strategy. Purpose & scope: evidence of natural chronobiotics (including resveratrol, quercetin, curcumin, honokiol, and nobiletin) in reshaping the asthmatic microenvironment, specifically focusing on subepithelial fibrosis and airway smooth muscle hyperplasia. We then propose a validation framework to distinguish genuine clock-dependent effects from pleiotropic pharmacological noise. Key challenges: studies fail to distinguish true clock-dependent modulation from clock-independent antioxidant and anti-inflammatory effects. Second, and more critically, the core clock target BMAL1 itself exhibits a fundamental dichotomy in allergic asthma-myeloid BMAL1 deficiency exacerbates acute eosinophilic inflammation but paradoxically suppresses chronic airway remodeling in a context-dependent manner. This underscores that correlative observations without genetic validation are insufficient, and that chronobiotic efficacy must be rigorously dissected across diverse asthmatic phenotypes. Future perspectives: To advance respiratory chronopharmacology, we propose a rigorous validation framework requiring macrophage-specific conditional knockout models (e.g., LysM-Cre; Bmal1 fl/fl). Finally, we highlight the integration of CD206-targeted inhalable nanocarriers, precision chronopharmacological dosing, and spatial transcriptomics as the definitive roadmap to translate natural chronobiotics into disease-modifying therapies for asthma.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1922510