HIF‑1α-YAP/TAZ signaling contributes to hypoxia‑induced alveolar epithelial differentiation in the yak lung

Hypoxia is a critical factor in the pathogenesis of pulmonary diseases, while the regenerative capacity of the alveolar epithelium is essential for lung repair. Yaks, a species well-adapted to high-altitude hypoxia, offer a unique model for studying epithelial adaptation under low-oxygen conditions. Lung tissues from yaks at successive developmental stages (0–1 year) were subjected to histological analysis and immunodetection of HIF-1α and YAP/TAZ. In vitro, primary alveolar type 2 (AT2) cells were isolated and cultured under hypoxic conditions to assess the effects of low oxygen on AT2 differentiation and to delineate the molecular regulatory interactions between HIF-1α and the Hippo signaling pathway. Yaks possess fully developed alveoli at birth, with an age-dependent expansion of alveolar surface area. By 3 months of age, the alveolar septa had become markedly thinner, accompanied by decreased expression of the AT2 cell markers proSP‑C and ABCA3, and increased expression of the AT1 cell markers AGER and AQP5. These findings highlight the dynamic developmental adaptation of yak alveoli to high‑altitude conditions. HIF-1α and YAP/TAZ were primarily distributed in the bronchial and alveolar epithelium, exhibiting dynamic and synchronous age-related changes. In vitro, induction of hypoxia in AT2 cells enhanced their differentiation into alveolar type 1 (AT1) cells. Mechanistically, hypoxia activated HIF-1α and downregulated the activity of the Hippo pathway, potentially contributing to increased nuclear translocation of YAP/TAZ. Inhibition of HIF-1α restored Hippo pathway activity and reduced YAP/TAZ expression. Simultaneously, HIF-1α and YAP/TAZ activation promoted AT2 cell differentiation, whereas their inhibition attenuated this process. Our study demonstrates that HIF-1α facilitates AT2-to-AT1 differentiation under hypoxia by interacting with the YAP/TAZ signaling axis, providing new insights into alveolar epithelial adaptation to hypoxia and potential therapeutic targets for pulmonary injury in high-altitude environments.