Preclinical evidence and multi-omics insights into the protective effects of epigallocatechin-3-gallate against high-fat diet-induced adverse health outcomes.

BACKGROUND: High-fat diet (HFD) consumption is associated with a range of adverse health outcomes, including dyslipidemia, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus (T2DM). Despite lifestyle interventions, patient adherence remains poor. Epigallocatechin-3-gallate (EGCG), a green tea catechin, shows therapeutic potential against HFD-induced adverse health outcomes. However, the systematic evaluation of its efficacy remains lacking. PURPOSE: By integrating meta-analysis, machine learning, in vivo evaluation, proteomics, and public single-cell RNA sequencing (scRNA-seq), this study aimed to systematically evaluate the therapeutic potential of EGCG against HFD-induced adverse health outcomes. METHODS: We meta-analyzed 79 rodent studies and developed machine learning models to explore outcome-specific dose and intervention-duration patterns for different metabolic outcomes. In the in vivo experiments, C57BL/6 mice were fed HFD and administered EGCG by gavage for 8 weeks. Additionally, liver and small intestine proteomics, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF) assessment, and UCell enrichment analysis of public NAFLD scRNA-seq data were performed. RESULTS: The meta-analysis of 79 preclinical studies showed that EGCG attenuated weight gain, dyslipidemia, hepatic lipid accumulation and injury, hyperglycemia, inflammation, and oxidative stress. Machine-learning analyses revealed outcome-specific differences in predicted dose and intervention-duration patterns across blood lipids, hepatic lipids, and blood glucose. Proteomics analysis indicated that glycerophospholipid metabolism was a common pathway for EGCG in both the liver and the small intestine. RT-qPCR and IF were used to assess the expression of molecules related to glycerophospholipid metabolism. Public scRNA-seq analysis provided a potential hepatic cell-subtype context for the proteomics-derived lipid-metabolism signature. CONCLUSION: This study has established a systematic preclinical evidence framework for evaluating the therapeutic potential of EGCG in addressing HFD-induced adverse health outcomes. Glycerophospholipid metabolism may be the common pathway through which EGCG protects the liver and small intestine.