Gene Signature-guided Drug Screening Identified Narciclasine as a Potential Therapeutic Drug for Renal Interstitial Fibrosis

Chronic Kidney Disease (CKD) is characterized by progressive tubulointerstitial fibrosis (TIF), a condition not adequately addressed by existing therapies. To identify potential compounds that could slow or halt the progression of TIF, we established gene signatures of TIF using published human CKD renal transcriptome data, followed by high-throughput screening of compounds that could reverse TIF-associated gene expression using the LINCS L1000 database. The natural compound Narciclasine (Ncls), extracted from daffodils, was identified as a promising candidate. We validated the effects of Ncls on a TGF-β1-induced fibrosis model in vitro using mouse primary tubular epithelial cells (TECs) and rat fibroblast cell line (NRK49F). Results demonstrated that Ncls significantly inhibited the pro-inflammatory and pro-fibrotic effects induced by TGF-β1 in TECs. Additionally, in fibroblasts, Ncls markedly suppressed the proliferation and activation induced by TGF-β1. These findings not only confirm the therapeutic potential of Ncls in managing TIF but also highlight the efficacy of gene signature-based screening in identifying drugs for the treatment of CKD.