Abstract / Summary
Abstract Background Idiopathic pulmonary fibrosis (IPF) is a life-threatening respiratory disorder with limited therapeutic alternatives. Current approved anti-fibrotic regimens mainly target fibroblast activation, yet fail to reverse established pulmonary fibrotic lesions. Epithelial-mesenchymal transition (EMT) serves as a critical upstream driver of IPF pathogenesis, which necessitates the development of mechanism-based therapeutic strategies. This study aimed to screen FDA-approved EMT inhibitors and dissect the underlying molecular mechanisms governing lung epithelial fibrogenesis. Methods Bioinformatic drug screening was performed using LINCS/CMAP algorithms, combined with transcriptomic analysis of human IPF clinical dataset GSE53845. Integrated transcriptomic and proteomic profiling was conducted on lung tissues from bleomycin (BLM)-challenged fibrotic mice. The BLM-induced pulmonary fibrosis mouse model was used for in vivo validation, and human A549 lung epithelial cells were applied for in vitro functional assays. We experimentally detected gene transcription, protein abundance and subcellular protein localization. All quantitative data were statistically analyzed using standard biomedical analytical approaches. Results Rapamycin (RAPA), a clinical immunosuppressant, was identified as a robust EMT suppressor. RAPA markedly reduced SFN mRNA and protein levels in A549 cells, restored MDM2 nuclear translocation, and accelerated ubiquitin-mediated p53 degradation. This signaling cascade blocked epithelial cell senescence and ultimately slowed pulmonary fibrosis progression. Conclusions RAPA ameliorates pulmonary fibrosis and restrains epithelial senescence by modulating the SFN-MDM2/p53 signaling axis. This work identifies an unreported anti-fibrotic regulatory pathway, and offers reliable preclinical evidence for drug repurposing of RAPA for IPF treatment. Trial registration No human-participant-related healthcare interventions were involved; Clinical trial number: not applicable.