Restrictive/obstructive pulmonary diseases are characterized by hypoxia. This condition activates the glycolytic pathway, resulting in the conversion of pyruvate into lactate and causing structural damage within pulmonary tissue. However, the molecular processes involved in restrictive/obstructive pulmonary diseases remain poorly understood. Our findings revealed that metabolites were significantly enriched in the Warburg effect pathway within plasma samples from children suffering from restrictive/obstructive pulmonary diseases. Consequently, we established a sustained hypoxia mice model. Compared to the control group, mice subjected to sustained hypoxia demonstrated increased lactylation in the lung tissue, accompanied by a significant upregulation of hypoxia-inducible-1a (Hif-1a) expression. Additionally, activation of the Wnt signaling pathway was observed. Subsequently, we employed SS-HPT (tobramycin-based hyperbranched polyaminoglycoside) nanocarriers to deliver Hif-1a-shRNA (shHif-1a). We found that under conditions of sustained hypoxia, the knockdown of Hif-1α significantly improved SpO2 levels and alleviated pulmonary dysfunction in our model. Our findings demonstrate that HIF-1α-mediated lactylation, which is upregulated in hypoxic lungs, plays a critical role in regulating Wnt signaling and inflammatory gene expression. Targeting this pathway may provide a therapeutic strategy for pulmonary dysfunction induced by prolonged hypoxia.Copyright © 2025. Published by Elsevier B.V.