Journal of endocrinological investigation · 2026
Global landscape of clinical trials and therapeutic targets in metabolic dysfunction-associated steatotic liver disease: an integrative multi-omics analysis.
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Mu Yanxi, Zhu Weixiong, Wei Zhihao, Guo Zhao, Chen Haofei, Cheng Yusheng, Zhou Wence
Аннотация
PURPOSE: To integrate global clinical trial data and multi-omics evidence in metabolic dysfunction-associated steatotic liver disease (MASLD) and evaluate therapeutic strategies, target distribution, tissue-specific safety profiles, and expression patterns across disease stages.
METHODS: MASLD-related trials registered between 1998 and May 2025 were retrieved from the Informa Database and analyzed by phase, intervention type, molecular target, and geographic distribution. Normal tissue expression of clinically relevant targets was assessed using HPA-RNA, HPA-Protein, and GTEx-RNA datasets to infer potential systemic safety. Bulk transcriptomic and single-cell RNA sequencing datasets from GEO were integrated to characterize target expression associated with disease and specific cell types during progression from metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC).
RESULTS: MASLD clinical trials increased markedly after 2010 but showed substantial imbalance across regions, phases, and intervention modalities. Pharmacological strategies predominated, with increasing emphasis on integrated regulation of metabolic, inflammatory, and fibrotic processes rather than single metabolic pathways. Multi-omics profiling revealed that many frequently investigated targets were also expressed in extrahepatic tissues and showed notable discordance between RNA and protein expression, suggesting heterogeneous systemic safety profiles. By integrating tissue specificity, expression changes related to disease, protein expression evidence, druggability, and translational evidence, AGTR1, DGAT1, FGFR4, KHK, NPC1L1, and PNPLA3 were prioritized as candidate targets. Single-cell analyses further indicated remodeling across disease stages and cell types, including enrichment of DGAT1 in immune cells during MASH and predominant KHK expression in hepatocytes with renewed elevation at the tumor stage.
CONCLUSIONS: This study links the global MASLD clinical trial landscape with multi-omics target characterization and identifies candidate targets with translational potential, providing a framework for target prioritization, safety assessment, and precision therapeutic development in MASLD.
METHODS: MASLD-related trials registered between 1998 and May 2025 were retrieved from the Informa Database and analyzed by phase, intervention type, molecular target, and geographic distribution. Normal tissue expression of clinically relevant targets was assessed using HPA-RNA, HPA-Protein, and GTEx-RNA datasets to infer potential systemic safety. Bulk transcriptomic and single-cell RNA sequencing datasets from GEO were integrated to characterize target expression associated with disease and specific cell types during progression from metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC).
RESULTS: MASLD clinical trials increased markedly after 2010 but showed substantial imbalance across regions, phases, and intervention modalities. Pharmacological strategies predominated, with increasing emphasis on integrated regulation of metabolic, inflammatory, and fibrotic processes rather than single metabolic pathways. Multi-omics profiling revealed that many frequently investigated targets were also expressed in extrahepatic tissues and showed notable discordance between RNA and protein expression, suggesting heterogeneous systemic safety profiles. By integrating tissue specificity, expression changes related to disease, protein expression evidence, druggability, and translational evidence, AGTR1, DGAT1, FGFR4, KHK, NPC1L1, and PNPLA3 were prioritized as candidate targets. Single-cell analyses further indicated remodeling across disease stages and cell types, including enrichment of DGAT1 in immune cells during MASH and predominant KHK expression in hepatocytes with renewed elevation at the tumor stage.
CONCLUSIONS: This study links the global MASLD clinical trial landscape with multi-omics target characterization and identifies candidate targets with translational potential, providing a framework for target prioritization, safety assessment, and precision therapeutic development in MASLD.