Computational Repurposing of Roxadustat Targeting HIF-1α and EGFR in Acute Lung Injury and Ischemic Hypoxia

Acute lung injury (ALI) and ischemic hypoxia (IH) remain significant clinical challenges due to their pathophysiologically linked conditions characterized by uncontrolled inflammation, alveolar damage, and severe oxygen deprivation. Despite the high disease burden, therapeutic options remain extremely limited, with Pentoxifylline (PTX) being one of the few available pharmacological agents offering only moderate efficacy; however, its limited therapeutic reach and adverse effects highlight a critical gap in the current pharmacological landscape and underscore the necessity for innovative, mechanism-driven therapeutic alternatives. This study investigates a novel repurposing strategy by evaluating the potential of Roxadustat (RXT), a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), initially approved for anemia in chronic kidney disease, in comparison with PTX, using an in silico multi-omics approach. We employed data mining from DrugBank, GeneCards, and SwissADME to identify intersecting targets of both drugs with ALI and IH. Protein-protein interaction (PPI) networks, KEGG pathway enrichment, and hub gene analyses revealed a distinct mechanistic advantage of RXT, revealing its significant engagement with key signaling pathways, especially EGFR and HIF-1α, as opposed to PTX. This mechanistic novelty is further validated through molecular docking, which confirmed higher binding affinities of RXT with EGFR and HIF-1α, indicating its stronger interactions than PTX. Molecular dynamics simulations over 100 ns further confirmed the greater stability and persistent residue-specific interactions of RXT-EGFR and RXT-HIF-1α complexes through RMSD, RMSF, and protein-ligand contact analyses. RXT consistently exhibited stronger and more stable interactions with critical residues, indicating greater pharmacodynamic potential. These findings are reinforced by the KEGG analysis, which highlights engagement of RXT with the HIF-1α signaling pathway, which is absent in PTX. Overall, the study results demonstrate RXT as a mechanistically relevant and pharmacodynamically strong candidate for drug repurposing with a superior prospect for managing ALI and IH. This study lays the groundwork for future preclinical validation and encourages translational exploration of RXT in hypoxia-related pulmonary conditions and disorders.