The FOXA transcription factors in allergic airway disease and asthma

The Forkhead box A (FOXA) transcription factors are pioneer factors that orchestrate diverse cellular and developmental processes. Within the respiratory system, FOXA1, FOXA2, and FOXA3 have emerged as modulators of pulmonary inflammation, with important implications for the pathogenesis of allergic asthma. In healthy lung and airways, FOXA1 and FOXA2 maintain epithelial integrity and promote ciliated cell development, thereby preserving homeostasis. FOXA2 additionally suppresses Th2 differentiation and goblet cell metaplasia and mucus overproduction. During allergic airway inflammation, FOXA2 expression is decreased and FOXA3 expression is induced by Th2 cytokines. Dysregulation of the FOXA regulatory network disrupts epithelial cell homeostasis and amplifies allergic inflammation, contributing to airway remodelling. Here we will review the potential mechanisms through which the FOXA family modulates airway inflammation, while also addressing gaps in current understanding, such as the context specific regulation of FOXA isoforms, their interplay with cytokine signalling pathways, and the translational relevance of these findings to therapeutic strategies in asthma.