Integrated Proteomics Reveals the Role of EPO-HBB Regulatory Axis in Lung Remodelling During Chronic Hypoxia Followed by De-Induction

Chronic hypoxia dysregulates pulmonary, vascular, and metabolic pathways. Most high-altitude studies primarily focus on acute exposure responses, while the molecular events governing de-induction after prolonged hypoxic stress are comparatively unexplored. Understanding chronic hypoxia-induced adaptations and recovery after de-induction will provide deeper insights into mechanisms of high-altitude acclimatization and maladaptation. In this study, we investigated global proteomic changes in rat lung tissue following chronic hypoxia exposure for 30 days (I30) and subsequent normoxic de-induction for 30 days (DI30). These changes were studied using integrated bioinformatics approaches and validated experimentally using Western blot analysis on rat lung tissue, with further confirmation in human plasma samples. To the best of our knowledge, this is the first study to identify and validate the EPO-HBB axis as a potential molecular signature associated with chronic hypoxia and the post-de-induction state. This novel finding provides important mechanistic insights into lung remodelling in chronic hypoxia and identifies EPO-HBB as a key regulatory axis relevant to high-altitude pathophysiology and recovery.