Transcriptotype-Driven Discovery of Apigenin as a Therapy against Cholestatic Liver Fibrosis: Through Inhibition of PANoptosis and Following Type-I Interferon Responses.

Cholangiopathies lack effective medicines and can progress into end-stage liver diseases. Mining natural product transcriptome databases for bioactive ingredients, which can reverse disease-associated transcriptomic phenotypes, holds promise as an effective approach for drug discovery. To identify disease-associated transcriptomic changes, we performed RNA-sequencing on bile duct ligation (BDL)-induced cholestatic liver fibrosis mice, as well as PBC and PSC patients, and found that PANoptosis and activation of type-I interferon (IFN) signaling were observed in BDL mice and patients with PBC and PSC. We then established a transcriptotype-driven screening system based on HERB and ITCM databases. Among 283 natural ingredients screened, apigenin (Api), which is widely distributed in varieties of food and medicinal plants, was screened out by our screen system since it reversed the expression pattern of key genes associated with PANoptosis and type-I IFN responses. In BDL, Abcb4 -/- , and DDC-fed mice, Api effectively ameliorated liver injuries, inflammation, and fibrosis. It also protected cholangiocytes from bile acid-stimulated PANoptosis, thus alleviating damage-associated molecular pattern-mediated activation of TBK1-NF-κB in macrophages. Additionally, Api directly inhibited type-I IFN-induced downstream inflammatory responses. Our study demonstrated the pathogenic roles of PANoptosis and type-I IFN signaling in cholestatic liver fibrosis and verified the feasibility of transcriptotype-based drug screening. Furthermore, this study revealed a novel anti-inflammatory mechanism of Api and identified it as a promising candidate for the treatment of cholestatic liver fibrosis.