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

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: This review critically evaluates the in vivo 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: We identify two major translational bottlenecks. First, the "pleiotropy dilemma": most existing in vivo 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.