The role of hypoxia-inducible factor-1α in COPD

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder defined primarily by persistent airflow limitation. Its pathogenesis involves multiple interrelated mechanisms, including hypoxia, inflammation, oxidative stress, airway remodeling, and pulmonary vascular remodeling. Hypoxia-inducible factor-1α (HIF-1α), the oxygen-sensitive functional subunit of the HIF-1 transcription factor complex, is stabilized under hypoxic conditions and mediates cellular adaptation to low-oxygen microenvironments by regulating glycolysis, angiogenesis, inflammatory responses, and metabolic reprogramming. Accumulating evidence indicates that HIF-1α can also be activated by non-hypoxic stimuli, including inflammatory cytokines, oxidative stress, cigarette smoke exposure, and several oxygen-independent signaling pathways. These findings support its role as a central molecular hub linking hypoxia, chronic inflammation, and metabolic dysregulation. In COPD, HIF-1α may contribute to disease onset and progression, as well as to COPD-related complications, by regulating airway inflammation, mucus hypersecretion, airway and pulmonary vascular remodeling, cellular senescence and apoptosis, and selected extrapulmonary manifestations. Several traditional Chinese medicine formulas and natural compounds have been reported to alleviate COPD-related pathological processes, partly through modulation of HIF-1α and its downstream signaling pathways. However, current evidence is derived mainly from preclinical studies or small clinical studies of limited methodological quality. Moreover, rigorous validation of HIF-1α-dependent mechanisms and high-quality randomized controlled trials remain lacking. This review summarizes the role of HIF-1α in the pathogenesis of COPD and its related complications. It also discusses recent advances in traditional Chinese medicine formulas and natural compounds that target HIF-1α, with the aim of providing a mechanistic basis for future COPD research and therapeutic development.