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Background <p>Metabolic dysfunction-associated steatohepatitis (MASH) is a severe progressive subtype of metabolic-related fatty liver disease that is defined by hepatic steatosis, hepatocyte damage, inflammation, and fibrosis. Alisol F 24-acetate (ALI), a triterpene derived from Rhizoma Alismatis, has anti-inflammatory and antioxidant properties. This study aimed to evaluate the therapeutic effects of ALI in a mouse model of MASH, RAW264.7 cells, and bone marrow-derived macrophages (BMDMs).</p> Methods <p>Levels of serum biochemicals, pathological changes in the liver, pyroptosis, and expression of the Kelch-like ECH-associated protein 1(KEAP1)/Nuclear factor E2-related factor 2 (NRF2) pathway were assessed in mice fed a methionine–choline-deficient (MCD) diet with different doses of ALI. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs were used to ascertain the potential mechanisms of ALI on macrophage polarization.</p> Results <p>We found that ALI supplementation in MCD-fed mice decreased liver pathology, lipid accumulation, inflammation, and fibrosis. Moreover, ALI could attenuate M1 polarization, promote M2 polarization, suppress pyroptosis, and reduce oxidative stress levels via the KEAP1/NRF2 signaling pathway in tissue samples. ALI also suppressed LPS-induced RAW264.7 cells and BMDMs pyroptosis by inhibiting NLRP3 activation and reducing the level of reactive oxygen species. Molecular docking results suggested that ALI could bind with KEAP1. Overexpressing <i>Keap1</i> weakened the effects of ALI on pyroptosis and affirmed a role associated with KEAP1/NRF2 pathways in macrophage.</p> Conclusion <p>Our findings suggest that ALI suppressed macrophage pyroptosis by targeting KEAP1/NRF2 interactions, providing reliable data on the protective mechanism of natural antioxidants against MASH.</p>

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Alisol F 24-acetate attenuated metabolic dysfunction-associated steatohepatitis by targeting the KEAP1/NRF2-mediated macrophage pyroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Zhiwu Dong,
  • Keliang Huang,
  • Weiyi Wu,
  • Lianxiang Xing,
  • Ying Zhang,
  • Xin Zhang,
  • Wenwei Yang,
  • Kewen Zhao

摘要

Background

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe progressive subtype of metabolic-related fatty liver disease that is defined by hepatic steatosis, hepatocyte damage, inflammation, and fibrosis. Alisol F 24-acetate (ALI), a triterpene derived from Rhizoma Alismatis, has anti-inflammatory and antioxidant properties. This study aimed to evaluate the therapeutic effects of ALI in a mouse model of MASH, RAW264.7 cells, and bone marrow-derived macrophages (BMDMs).

Methods

Levels of serum biochemicals, pathological changes in the liver, pyroptosis, and expression of the Kelch-like ECH-associated protein 1(KEAP1)/Nuclear factor E2-related factor 2 (NRF2) pathway were assessed in mice fed a methionine–choline-deficient (MCD) diet with different doses of ALI. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs were used to ascertain the potential mechanisms of ALI on macrophage polarization.

Results

We found that ALI supplementation in MCD-fed mice decreased liver pathology, lipid accumulation, inflammation, and fibrosis. Moreover, ALI could attenuate M1 polarization, promote M2 polarization, suppress pyroptosis, and reduce oxidative stress levels via the KEAP1/NRF2 signaling pathway in tissue samples. ALI also suppressed LPS-induced RAW264.7 cells and BMDMs pyroptosis by inhibiting NLRP3 activation and reducing the level of reactive oxygen species. Molecular docking results suggested that ALI could bind with KEAP1. Overexpressing Keap1 weakened the effects of ALI on pyroptosis and affirmed a role associated with KEAP1/NRF2 pathways in macrophage.

Conclusion

Our findings suggest that ALI suppressed macrophage pyroptosis by targeting KEAP1/NRF2 interactions, providing reliable data on the protective mechanism of natural antioxidants against MASH.