Hypoxia: a critical pathophysiological driver in respiratory inflammatory diseases

Hypoxia is a central pathophysiological driver of inflammatory airway diseases, shaping disease progression largely through hypoxia-inducible factor 1α (HIF-1α) signaling. Across these disorders, hypoxia exacerbates airway inflammation through shared mechanisms. As a key signaling hub, HIF-1α disrupts epithelial barrier integrity and initiates inflammatory cascades; reprograms immune responses, promoting the activation and trafficking of eosinophils, T cells, and macrophages while reshaping cytokine profiles, to drive tissue injury; and accelerates airway remodeling, thereby worsening airflow limitation and perpetuating inflammatory cycles. Realizing effective targeted therapies will require rigorous validation of HIF-1α as a therapeutic node and the development of disease-tailored interventions aligned with distinct pathological features. In parallel, strengthened translational and clinical research on hypoxia is essential to build a robust evidence base for practice. This review synthesizes hypoxia-driven mechanisms shared across airway diseases, articulates a unifying framework for HIF-1α signaling across pathological contexts, and highlights the therapeutic implications of fundamental discoveries. By addressing the paucity of cross-disease analyses of hypoxia pathways, it provides both a conceptual foundation and a practical roadmap for developing precise and efficient targeted therapies for inflammatory respiratory diseases.