Molecular Clocks in Translational Roadmap for Circadian-Based Therapeutics in Lung Diseases

The lung contains a robust peripheral circadian clock that regulates airway tone, epithelial barrier integrity, immune cell trafficking, and metabolic homeostasis through transcriptional-translational feedback loops involving BMAL1, CLOCK, PER, CRY, REV-ERBα, and RORα. Disruption of this molecular clock is increasingly recognized as a central pathogenic mechanism across pulmonary diseases. Inflammatory signaling, cigarette smoke, hyperoxia, infection, and developmental stress suppress core clock components, dampen clock-controlled gene rhythms, and drive persistent inflammation, impaired mucociliary clearance, oxidative injury, epithelial-mesenchymal transition, fibrosis, and tumor progression. Altered rhythmicity of BMAL1, REV-ERBα, PER2, and RORα has been reported in asthma, COPD, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, pneumonia, and lung cancer, correlating with characteristic diurnal fluctuations in symptoms and lung function. This narrative review integrates current evidence linking chronodisruption to pulmonary pathobiology and highlights emerging therapeutic strategies aimed at restoring circadian homeostasis. Small-molecule modulators of REV-ERBα, RORα, CRY, PER, CLOCK, and metabolic pathways (NAD⁺-SIRT1 axis), in conjunction with chronotherapy-based timing of standard treatments, show potential to reestablish rhythmic gene expression and attenuate inflammation and tissue remodeling. The lung circadian clock is a central regulator of respiratory physiology and a promising therapeutic target in chronic lung disease. Strategies that restore rhythmicity, including clock-directed small molecules and time-optimized therapies, offer emerging opportunities to reduce inflammation, prevent maladaptive remodeling, and improve clinical outcomes.