Multiscale Transcriptomic Reversal and Structural Docking Identify Repurposing Candidates for Idiopathic Pulmonary Fibrosis

Drug-induced reversal of disease expression can support repurposing, but reversal alone ignores cohort dependence, cell context and safety. We derived a directionally concordant idiopathic pulmonary fibrosis (IPF) signature across three lung cohorts, constructed an adaptive signed h-backbone, localized hubs by donor-level single-cell pseudobulk analysis, and queried LINCS L1000 before FDA, target-direction and structural plausibility gates. Among 12,417 shared genes, 4,027 were significant and sign-concordant; 89,326 single cells linked network hubs to endothelial, macrophage and injured epithelial compartments. Of 10,000 LINCS signatures, 4,991 met strict reversal criteria and 69 perturbagens matched active FDA products. Integrated ranking prioritized pentoxifylline and a cyclic-nucleotide phosphodiesterase hypothesis. PDE3A redocking reproduced the crystallographic pose (median RMSD 0.86 Å), while pentoxifylline showed reproducible PDE3A and modeled PDE7B poses. Clinically unsuitable glucocorticoid reversers demonstrate that expression reversal requires multi-gate interpretation; candidates remain experimental hypotheses.