Circadian clock regulation in lung health and disease: molecular mechanisms and therapeutic opportunities.

Abstract

Circadian rhythms are endogenous time-keeping mechanisms that organize physiological and cellular functions into approximately 24-hour cycles. These rhythms are generated by conserved molecular clocks composed of interconnected transcription-translation feedback loops involving core regulators such as CLOCK, BMAL1, PERIOD, CRYPTOCHROME, REV-ERB, and ROR proteins. While circadian regulation is best known for governing sleep-wake behavior, mounting evidence demonstrates that peripheral clocks exert critical control over organ-specific physiology. The lung represents a highly rhythmic tissue in which local circadian oscillators coordinate airway tone, immune surveillance, inflammatory signaling, epithelial repair, and metabolic homeostasis. Disruption of circadian timing arising from genetic alterations, environmental stressors, shift work, irregular light exposure, or chronic inflammation has emerged as an important contributor to the development and progression of multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, acute lung injury, sleep-disordered breathing, and lung cancer. At the mechanistic level, dysregulation of clock genes alters inflammatory pathways, oxidative stress responses, mitochondrial metabolism, and cell-cycle control, thereby exacerbating tissue injury and impairing resolution and repair. Recognition of these temporal influences has prompted growing interest in circadian-based therapeutic strategies. Chronotherapy, which aligns drug administration with endogenous biological rhythms, and pharmacological targeting of clock components such as REV-ERBs and RORs, offer promising avenues to improve treatment efficacy while limiting adverse effects. This review integrates current insights into circadian clock architecture, lung-specific regulation, disease mechanisms, and therapeutic potential, highlighting circadian biology as a critical yet underutilized dimension of respiratory medicine. See also the graphical abstract(Fig. 1).