Club cells in asthma: Multifunctional regulators of airway integrity and emerging therapeutic targets

Asthma is a chronic inflammatory airway disease characterized by complex interactions among multiple cell types within the local microenvironment. Among these, Club cells (CCs) are specialized airway epithelial cells that play key roles in maintaining airway integrity and immune homeostasis. They contribute to epithelial repair, barrier maintenance, innate defense, circadian control, and xenobiotic metabolism. Accumulating evidence also indicates that CCs exhibit substantial functional heterogeneity and may act as both protectors of bronchiolar integrity and context-dependent drivers of airway inflammation and remodeling. However, the roles of CCs in asthma remain incompletely understood, as current evidence is fragmented across different subfields of respiratory research. This review synthesizes current knowledge on the multifaceted roles of CCs by highlighting their critical regenerative and immune-regulatory functions pertaining to the pathobiology of asthma. We further discuss how loss of protective mediators such as SCGB1A1, dysregulated club-to-goblet cell differentiation, the release of alarmins, and damage-associated molecular patterns may link CCs dysfunction to inflammatory endotypes, mucus hypersecretion and airway remodeling. Finally, emerging CC-targeted therapeutic strategies are also summarized, highlighting their potential to move beyond symptom management toward precision interventions that restore bronchiolar homeostasis.