Beta-lapachone ameliorates the progression of primary sclerosing cholangitis pathogenesis in rodent models

Abstract

Aims: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and severe fibrosis for which effective treatment options are currently lacking. In this study, we explored the potential of beta-lapachone (βL) as a drug candidate for PSC therapy. Materials and methods: We employed an animal model fed a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to assess the preventive and therapeutic effects of βL. The beneficial effects of βL on PSC pathogenic characteristics, including blood biomarkers, inflammation, and fibrosis, were determined by assessing relevant parameters. Differential gene expression between each group was analyzed by RNA sequencing of liver tissues. Mdr2？/？ mice were utilized to explore the involvement of Abcb4 in the βL-induced improvement of PSC pathogenesis. Key findings: βL effectively inhibited key features of PSC pathogenesis, as demonstrated by reduced blood biomarkers and improved pathogenic characteristics. Treatment with βL significantly mitigated DDC-induced apoptosis, cell proliferation, inflammation, and fibrosis. Analysis of differential gene expression confirmed a new insight that βL could stimulate the expression of genes related to NAD synthesis and Abcb4. Indeed, βL-induced NAD exhibited effective functioning, as evidenced by enhanced sirt1/3 and acetyl-lysine levels, leading to improved mitochondrial stability. The role of Abcb4 in response to βL was confirmed in Mdr2/Abcb4 KO mice, where the beneficial effects of βL were abolished. Significance: This study provided a new concept for PSC treatment, suggesting that pharmacological stimulation of the NAD synthetic pathway and Abcb4 via βL ameliorates PSC pathogenesis.