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Background <p>Sini-San (SNS), a classical traditional Chinese medicinal formula, has demonstrated promising potential in mitigating the progression of liver fibrosis (LF). Increasing evidence highlights that disruption of bile acids (BAs) homeostasis is critically involved in the pathogenesis and progression of LF, suggesting that targeting BAs metabolism could represent a therapeutic strategy. This study aimed to explore whether the protective effects of SNS against LF are mediated through modulation of BAs metabolism and associated regulatory pathways.</p> Methods <p>The chemical constituents of SNS were characterized using high-performance liquid chromatography (HPLC). LF models were established in mice through intraperitoneal injection of carbon tetrachloride (CCl<sub>4</sub>) or feeding a high-fat, high-sugar (HFHS) diet. SNS was administered orally. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hydroxyproline (HYP) levels were measured, and liver histopathology was evaluated by hematoxylin–eosin (HE), Masson and TUNEL staining. The expression of fibrosis- and apoptosis-associated markers (Collagen-1, α-SMA, Bcl-2, Bax, and Caspase-3) was assessed by RT-qPCR and Western blotting. Serum BAs profiles were analyzed using LC–MS/MS, and molecules involved in BA metabolism (Fxr, Cyp7a1, Cyp27a1, Bsep, Ntcp, Asbt and OATP) were examined. Gut microbiota composition was analyzed through 16S rRNA gene sequencing. To investigate the mechanisms by which SNS regulates BAs homeostasis, additional experiments were conducted under choline chelation, pseudo-sterile conditions, and in <i>fxr</i><sup><i>−/−</i></sup> mice.</p> Results <p>In LF mice induced by CCl<sub>4</sub> or HFHS diet, significant alterations were observed in BAs levels and composition. The expression of BAs-synthesizing enzymes (CYP7A1, CYP27A1), BAs transporters (<i>Bsep, Ntcp, Asbt</i> and <i>Oatp</i>), and the feedback regulatory receptor FXR was markedly dysregulated. Meanwhile, gut microbiota abundance and composition were also significantly disrupted, indicating a disturbance of BAs homeostasis. SNS treatment effectively alleviated liver injury and fibrosis, corrected BAs imbalance, regulated the expression of BAs-related genes, and restored microbial diversity. However, the antifibrotic effects of SNS were reversed by choline chelation, antibiotic treatment, and <i>fxr</i> knockout.</p> Conclusions <p>SNS may exert anti-hepatic fibrosis effects by modulating BAs metabolism and gut-liver axis pathways, ultimately restoring BAs homeostasis. These findings provide new insights into the therapeutic mechanisms of SNS and suggest its potential as a multitargeted strategy for LF treatment.</p>

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Regulatory effects of Sini-San on bile acid homeostasis in the enterohepatic circulation of mice with liver fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Fangsi Zhu,
  • Yijie Ding,
  • Luyun Chen,
  • Rou Fang,
  • Chengfeng Huang,
  • En Liu,
  • Yingrui Wang,
  • Yong Su,
  • Chaoliang Ge

摘要

Background

Sini-San (SNS), a classical traditional Chinese medicinal formula, has demonstrated promising potential in mitigating the progression of liver fibrosis (LF). Increasing evidence highlights that disruption of bile acids (BAs) homeostasis is critically involved in the pathogenesis and progression of LF, suggesting that targeting BAs metabolism could represent a therapeutic strategy. This study aimed to explore whether the protective effects of SNS against LF are mediated through modulation of BAs metabolism and associated regulatory pathways.

Methods

The chemical constituents of SNS were characterized using high-performance liquid chromatography (HPLC). LF models were established in mice through intraperitoneal injection of carbon tetrachloride (CCl4) or feeding a high-fat, high-sugar (HFHS) diet. SNS was administered orally. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hydroxyproline (HYP) levels were measured, and liver histopathology was evaluated by hematoxylin–eosin (HE), Masson and TUNEL staining. The expression of fibrosis- and apoptosis-associated markers (Collagen-1, α-SMA, Bcl-2, Bax, and Caspase-3) was assessed by RT-qPCR and Western blotting. Serum BAs profiles were analyzed using LC–MS/MS, and molecules involved in BA metabolism (Fxr, Cyp7a1, Cyp27a1, Bsep, Ntcp, Asbt and OATP) were examined. Gut microbiota composition was analyzed through 16S rRNA gene sequencing. To investigate the mechanisms by which SNS regulates BAs homeostasis, additional experiments were conducted under choline chelation, pseudo-sterile conditions, and in fxr−/− mice.

Results

In LF mice induced by CCl4 or HFHS diet, significant alterations were observed in BAs levels and composition. The expression of BAs-synthesizing enzymes (CYP7A1, CYP27A1), BAs transporters (Bsep, Ntcp, Asbt and Oatp), and the feedback regulatory receptor FXR was markedly dysregulated. Meanwhile, gut microbiota abundance and composition were also significantly disrupted, indicating a disturbance of BAs homeostasis. SNS treatment effectively alleviated liver injury and fibrosis, corrected BAs imbalance, regulated the expression of BAs-related genes, and restored microbial diversity. However, the antifibrotic effects of SNS were reversed by choline chelation, antibiotic treatment, and fxr knockout.

Conclusions

SNS may exert anti-hepatic fibrosis effects by modulating BAs metabolism and gut-liver axis pathways, ultimately restoring BAs homeostasis. These findings provide new insights into the therapeutic mechanisms of SNS and suggest its potential as a multitargeted strategy for LF treatment.