Pharmacological regulation of airway ciliary motility: endogenous mediators, pharmaceutical agents, and natural compounds with a focus on ginsenoside Rd

Mucociliary clearance (MCC) is a central component of airway innate defense, and its impairment contributes to respiratory morbidity in chronic obstructive pulmonary disease, asthma, primary ciliary dyskinesia, and chemotherapy-induced ciliary dysfunction. Reduced ciliary motility increases susceptibility to infection, making pharmacological enhancement of airway cilia an attractive yet underexplored strategy. Ciliary activity is regulated by intracellular signaling pathways including cAMP-, Ca2+-, nitric oxide-, and Cl⁻- signaling, which converge on axonemal dynein to control ciliary beat frequency, bend angle, and bend distance. Although numerous endogenous mediators, pharmaceutical agents, and natural compounds stimulate ciliary motility, these findings remain fragmented and lack systematic integration. This review classifies airway ciliary activators by signaling mechanism and discusses their translational relevance in diseases characterized by impaired MCC. Particular emphasis is placed on ginsenoside Rd as a representative natural compound that enhances ciliary motility through activation of estrogen receptor β and potentiation of the P2 X 7 receptor and ameliorates chemotherapy-induced ciliary motility disturbance. Its preferential lung accumulation supports translational potential. By integrating intracellular signaling mechanisms with translational perspectives, this review highlights pharmacological activation of airway cilia, including strategies derived from natural compounds and herbal medicines, as a meaningful and underexplored approach to enhancing MCC, and outlines key knowledge gaps and future research directions.