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Updated: Mar 30, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
METTL1-deficient mesenchymal stem cells protect against metabolic-associated fatty liver disease by increasing NAMPT
Jiang Du1,2, Yuxuan Zhang1,2, Chiheng Wang1,2
1Henan Collaborative Innovation Center of Stem Cells and Biotherapy, School of Medical Engineering, Henan Medical University (Xinxiang Medical University), Xinxiang 453003, China.
Background:
Genetically modified mesenchymal stem cells (MSCs) have been shown to enhance their therapeutic properties, offering more effective treatment options for various diseases, including metabolic associated fatty liver disease (MASLD). The m7G methyltransferase METTL1 plays a critical role in regulating RNA splicing, stability, and translation. This study presents our findings on METTL1 modified human umbilical cord MSCs, emphasizing their therapeutic effects and the mechanisms involved in treating MASLD.
Methods:
METTL1 knockdown MSCs were generated via lentiviral shRNA. Key characteristics, including senescence, proliferation, cell cycle, and apoptosis, were assessed in vitro. A high-fat diet (HFD)-induced MASLD mouse model was used to evaluate the effects of MSC transplantation through serological, biochemical, and pathological analyses. Molecular mechanisms were explored using immunofluorescence (IF), Western blotting (WB), and quantitative PCR (qPCR).
Results:
Our results indicate that METTL1-deficient MSCs exhibit reduced proliferative capacity and increased susceptibility to senescence and apoptosis. Remarkably, these MSCs significantly decreased lipid accumulation in both in vitro and in vivo MASLD models. We found that METTL1-deficient MSCs secrete higher levels of NAMPT, which activates SIRT1, leading to the inhibition of SREBP1-mediated lipogenic genes. Inhibition of NAMPT reversed the protective effects of METTL1-deficient MSCs against MASLD-related lipid metabolic disorders. Furthermore, overexpression of METTL1 in MSCs exacerbated lipid metabolic disorders in MASLD mice by inhibiting the NAMPT/SIRT1/SREBP1 signaling pathway.
Conclusion:
METTL1-deficient MSCs alleviate MASLD-associated lipid metabolic disorders via NAMPT secretion. This suggests that genetically modified MSCs targeting METTL1 may represent a promising therapeutic strategy for the treatment of MASLD.
