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

TL;DR

Alisol F 24-acetate reduces liver damage in a mouse model of fatty liver disease by targeting a key antioxidant pathway in immune cells.

Contribution

ALI's novel mechanism of suppressing macrophage pyroptosis via KEAP1/NRF2 pathway in MASH is newly demonstrated.

Findings

ALI reduced liver pathology, inflammation, and fibrosis in MASH mice.

ALI suppressed macrophage pyroptosis and oxidative stress via KEAP1/NRF2 pathway.

Molecular docking confirmed ALI's interaction with KEAP1.

Abstract

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).

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13020-025-01322-8.

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