Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Liquiritigenin alleviates liver fibrosis through the nuclear receptor subfamily 1 group D member 1-regulated ferroptosis signaling pathway.
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Guo Xin, Huang Bao-Nian, Zuo Jing-Yu, Tai Yi, Liu Xue-Kun, Du Rui, Jin Xue-Jun
Аннотация
BACKGROUND: Liver fibrosis can be accelerated by oxidative stress and inflammatory damage. The effect of liquiritigenin (LQ) on ferroptosis in liver fibrosis is what this research intends to explore.
METHODS: Mouse models of liver fibrosis were created through intraperitoneal injection of carbon tetrachloride (CCl4) and silencing of NR1D1. Subsequently, RNA sequencing was employed to infer the liver fibrosis signaling network. 16S rRNA analysis was used to assess LQ's efficacy in improving liver fibrosis. AML12 cells were treated with LQ and H2O2/Erastin, and siRNA-NR1D1 was transfected into mouse primary hepatocytes in vivo. The interplay between NR1D1 and SLC7A11 promoter was investigated via dual-luciferase assay. Mouse bone marrow-derived macrophages (BMDMs) were treated with LPS/Erastin and LQ, and siRNA-NR1D1 was transfected into them.
RESULTS: RNA sequencing indicated that in the mouse models induced by CCl₄, the NR1D1/ SLC7A11/ferroptosis/mitophagy pathway changed significantly, which was crucial for LQ-mediated hepatoprotection. LQ could effect on gut microbiota diversity and composition. After knocking down NR1D1 via shRNA, the protein and mRNA levels of SLC7A11 in mouse livers decreased significantly, and ferroptosis was exacerbated. The absence of NR1D1 in hepatocytes impaired the inhibitory effect of LQ on the SLC7A11-mediated ferroptosis pathway. It was shown that NR1D1 can directly bind to the SLC7A11 promoter. Moreover, LQ can reduce ferroptosis in BMDMs, thereby diminishing the inflammatory response.
CONCLUSIONS: These findings suggest that LQ can inhibit ferroptosis by modulating the NR1D1-SLC7A11 signaling pathway in liver fibrosis. LQ represents a promising therapeutic candidate and its mechanism offers a novel strategy for treating liver fibrosis.
METHODS: Mouse models of liver fibrosis were created through intraperitoneal injection of carbon tetrachloride (CCl4) and silencing of NR1D1. Subsequently, RNA sequencing was employed to infer the liver fibrosis signaling network. 16S rRNA analysis was used to assess LQ's efficacy in improving liver fibrosis. AML12 cells were treated with LQ and H2O2/Erastin, and siRNA-NR1D1 was transfected into mouse primary hepatocytes in vivo. The interplay between NR1D1 and SLC7A11 promoter was investigated via dual-luciferase assay. Mouse bone marrow-derived macrophages (BMDMs) were treated with LPS/Erastin and LQ, and siRNA-NR1D1 was transfected into them.
RESULTS: RNA sequencing indicated that in the mouse models induced by CCl₄, the NR1D1/ SLC7A11/ferroptosis/mitophagy pathway changed significantly, which was crucial for LQ-mediated hepatoprotection. LQ could effect on gut microbiota diversity and composition. After knocking down NR1D1 via shRNA, the protein and mRNA levels of SLC7A11 in mouse livers decreased significantly, and ferroptosis was exacerbated. The absence of NR1D1 in hepatocytes impaired the inhibitory effect of LQ on the SLC7A11-mediated ferroptosis pathway. It was shown that NR1D1 can directly bind to the SLC7A11 promoter. Moreover, LQ can reduce ferroptosis in BMDMs, thereby diminishing the inflammatory response.
CONCLUSIONS: These findings suggest that LQ can inhibit ferroptosis by modulating the NR1D1-SLC7A11 signaling pathway in liver fibrosis. LQ represents a promising therapeutic candidate and its mechanism offers a novel strategy for treating liver fibrosis.