Integrated Transcriptomic and Metabolomic Analyses Reveal the Protective Mechanism of Icaritin Against High‐Fat Diet‐Induced Metabolic Dysfunction‐Associated Steatotic Liver Disease in Mice

Feb 10, 2026FASEB journal : official publication of the Federation of American Societies for Experimental Biology

How Icaritin helps protect mice from fatty liver disease caused by a high-fat diet, shown by combined gene and metabolism analyses

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Abstract

Icaritin (ICT) treatment significantly improved liver health in a mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD).

ICT reduced liver fat accumulation and improved lipid profiles in mice fed a high-fat diet.
The treatment reversed the downregulation of genes associated with cholesterol transport.
ICT altered the expression profiles of key metabolic pathways, particularly in glycogen and lipid metabolism.
In vitro studies showed that ICT also reversed the suppression of the GSTA1 gene in liver cells.
A direct interaction between ICT and the GSTA1 protein was confirmed through molecular docking and thermal shift assays.
Knocking down GSTA1 in liver cells negated the protective effects of ICT, indicating its crucial role in the treatment.

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease. Icaritin (ICT) has demonstrated potential hepatoprotective effects, while its protective mechanisms on MASLD are still unclear. This study aims to investigate the therapeutic efficacy of ICT against MASLD and elucidate its underlying molecular mechanisms. A MASLD mouse model was established via a high-fat diet (HFD) for 12 weeks, with or without gavage of ICT for 4 weeks. Palmitic acid (PA) was used to induce an in vitro model in AML12 hepatocytes. Histological, biochemical, transcriptomic (RNA-Seq), metabolomic, and lipidomic analyses were employed. Key targets were validated using molecular docking, cellular thermal shift assay (CETSA), and gene knockdown approaches. ICT treatment ameliorated HFD-induced hepatic steatosis, dyslipidemia, and reversed the suppression of reverse cholesterol transport genes. The expression of key genes identified by RNA sequencing was verified by RT-qPCR. Integration of transcriptomics and metabolomics revealed that ICT reshaped transcriptomic and metabolomic profiles, highlighting key pathways in glycogen metabolism, lipid metabolism, and antioxidant responses. Both in vivo and in vitro, ICT reversed the downregulation of GSTA1 expression. Molecular docking and CETSA confirmed a direct binding interaction between ICT and the GSTA1 protein. GSTA1 knockdown in AML12 cells abolished the protective effects of ICT. ICT alleviates MASLD progression by targeting GSTA1-mediated metabolic reprogramming, providing a novel mechanistic foundation for ICT as a promising candidate for MASLD treatment.

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Integrated Transcriptomic and Metabolomic Analyses Reveal the Protective Mechanism of Icaritin Against High‐Fat Diet‐Induced Metabolic Dysfunction‐Associated Steatotic Liver Disease in Mice

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