Repurposing omics data to discover therapeutics for steatohepatitis

Zhang, Birong 2024. Repurposing omics data to discover therapeutics for steatohepatitis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background: Approximately 5% of adults in the world suffer from metabolic dysfunction-associated steatohepatitis, which is the leading cause of liver failure and the primary indication for liver transplantation. Despite its adverse consequences and huge economic burden on healthcare, therapeutic options for MASH remain severely limited, with only one drug under accelerated approval. This thesis aims to address this complex disease by proposing a new drug repurposing approach to find promising drug candidates. Methods: A comprehensive transcriptome analysis was conducted on 596 human liver biopsies to establish the MASH expression landscape. The Sum of Deviations from Inverse Universal Mapping (SODIUM), a novel signature-based drug repurposing method, was developed to interrogate the relationships between the derived MASH disease signature and 168,816 drug-induced transcriptional profiles. To evaluate SODIUM's performance, a rigorous validation framework was established, comprising a curated dataset of 43 diseases and 77,217 drug profiles, against which three independent benchmarking standards were implemented. Therapeutic candidates were subsequently validated through a multimodal approach, incorporating MASLD cell studies, MASH animal models, bulk and singlenucleus RNA-Seq analysis. Results: Transcriptomic analysis revealed a highly discriminative 187-gene MASH signature that exhibited robust diagnostic performance, achieving an average AUC of 0.878 when validated across independent cohorts. In systematic benchmarking against six established drug repurposing methodologies, SODIUM demonstrated superior performance across all three evaluation standards. Implementation of SODIUM to target the MASH disease signature identified 232 potential therapeutic compounds, with remarkable clinical relevance evidenced by 3 of the top 10 predicted candidates currently undergo randomized clinical trials for MASH. Most notably, our leading candidates, Artesunate and Cabergoline, exhibited multifaceted beneficial effects, demonstrating significant reductions in hepatic steatosis, marked attenuation of inflammatory markers, and substantial improvement in fibrosis in preclinical models.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	23 January 2025
Last Modified:	23 Jan 2025 14:40
URI:	https://orca.cardiff.ac.uk/id/eprint/175537

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