Experimental cell research · 2026
Indole-3-lactic acid attenuates hepatic stellate cell pyroptosis and liver fibrosis associated with NLRP3 signaling.
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Shang Fei, Cui XiangYu, Wang Bin, Liu FengChao, Tian QiuJu
Аннотация
BACKGROUND AND AIMS: Hepatic stellate cell (HSC) pyroptosis is increasingly recognized as an important contributor to liver inflammation and fibrosis; however, the role of endogenous metabolites in regulating this process remains incompletely understood. This study aimed to investigate the potential function and mechanism of the tryptophan-derived metabolite indole-3-lactic acid (ILA) in HSC pyroptosis and liver fibrosis.
METHODS: Serum ILA from cirrhosis patients was quantified by Gas Chromatography-Mass Spectrometry. In vitro, HSC pyroptosis induced by lipopolysaccharide (LPS) and nigericin was used to assess the effects of ILA, an aryl hydrocarbon receptor (AHR) antagonist, siRNA-mediated AHR knockdown, and NLRP3 overexpression. In vivo, a carbon tetrachloride (CCl4)-induced liver fibrosis model was established, and mice were treated with ILA with or without adeno-associated virus-mediated hepatic NLRP3 overexpression.
RESULTS: ILA levels were significantly reduced in patients with cirrhosis compared to controls. In vitro, ILA attenuated pyroptosis-associated changes in HSCs and was associated with activation of AHR signaling and modulation of the NLRP3 inflammasome pathway. These effects were diminished by AHR blockade or NLRP3 overexpression. In vivo, ILA was associated with improved liver histology and reduced markers of hepatic pyroptosis and inflammation, whereas NLRP3 overexpression partially attenuated these effects.
CONCLUSION: ILA could suppress HSC pyroptosis and alleviate liver fibrosis, potentially through AHR-dependent inhibition of NLRP3. These findings provide insight into the role of tryptophan-derived metabolites in liver fibrosis and suggest that ILA may represent a potential therapeutic candidate.
METHODS: Serum ILA from cirrhosis patients was quantified by Gas Chromatography-Mass Spectrometry. In vitro, HSC pyroptosis induced by lipopolysaccharide (LPS) and nigericin was used to assess the effects of ILA, an aryl hydrocarbon receptor (AHR) antagonist, siRNA-mediated AHR knockdown, and NLRP3 overexpression. In vivo, a carbon tetrachloride (CCl4)-induced liver fibrosis model was established, and mice were treated with ILA with or without adeno-associated virus-mediated hepatic NLRP3 overexpression.
RESULTS: ILA levels were significantly reduced in patients with cirrhosis compared to controls. In vitro, ILA attenuated pyroptosis-associated changes in HSCs and was associated with activation of AHR signaling and modulation of the NLRP3 inflammasome pathway. These effects were diminished by AHR blockade or NLRP3 overexpression. In vivo, ILA was associated with improved liver histology and reduced markers of hepatic pyroptosis and inflammation, whereas NLRP3 overexpression partially attenuated these effects.
CONCLUSION: ILA could suppress HSC pyroptosis and alleviate liver fibrosis, potentially through AHR-dependent inhibition of NLRP3. These findings provide insight into the role of tryptophan-derived metabolites in liver fibrosis and suggest that ILA may represent a potential therapeutic candidate.