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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Rattus norvegicus

PROVIDER: GSE269356 | GEO | 2025/06/12

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE269356_Ncls_NRK49F_all_sample_Matrix_Count.xlsx	Xlsx
	GSE269356_Ncls_TECs_all_sample_Matrix_Count.xlsx	Xlsx

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Project description:Background: Increased Galectin 3-binding protein (Lgals3bp) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that Lgals3bp regulates the TGF-β1 signaling pathway. Methods: The expression levels of Lgals3bp and TGF-β1 were analyzed in patients with non-alcoholic steatohepatitis (NASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the Lgals3bp-TGF-β1 axis. Moreover, the effects of altered TGF-β1 signaling in chronic inflammatory conditions were investigated in conditional Lgals3bp-knockin and Lgals3bp-knockout mice. Results: In patients with NASH and HCC, the levels of Lgals3bp and TGF-β1 exhibited positive correlations. Stimulation of Lgals3bp by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of Lgals3bp in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific Lgals3bp knock-in mice, with increased TGF-β1 levels. Lgals3bp directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. Lgals3bp deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis. Finally, Lgals3bp depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1. Conclusion: Lgals3bp plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.

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

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