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<p>Hepatocellular carcinoma (HCC), often arising from liver fibrosis in nonalcoholic fatty liver disease (NAFLD), remains a leading cause of cancer-related death. Targeting the gut–liver axis offers new therapeutic opportunities to prevent this progression. In this study, colon-targeted chitosan/pectin-based nanoparticles loaded with Astragalus polysaccharide (APs-CS/PT-NPs) were developed to modulate gut microbiota and inhibit liver tumorigenesis. The nanoparticles exhibited robust physicochemical stability and pH-responsive release. In vivo, oral administration of APs-CS/PT-NPs attenuated hepatic steatosis, reduced inflammatory cytokines, and suppressed NAFLD-induced HCC development. 16&#xa0;S rRNA sequencing revealed restoration of microbial diversity and enhanced production of short-chain fatty acids, especially acetate. Mechanistically, transcriptomic profiling and functional analysis identified acetate as a key mediator, acting via G-protein-coupled receptor 43 (GPR43) to inhibit the NF-κB pathway. These results highlight the therapeutic potential of APs-CS/PT-NPs in modulating the gut–liver axis, rebalancing intestinal microbiota, and suppressing pro-inflammatory signaling. This nanoparticle-based strategy offers a promising food-derived preventive intervention for liver fibrosis–HCC transition.</p> Graphical Abstract <p></p>

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Colon-Targeted astragalus polysaccharide nanoparticles prevent NAFLD-Driven hepatocarcinogenesis via microbiota remodeling and NF-κB Inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • Dan Liu,
  • Runtian Li,
  • Mingzhu Li,
  • Ying Liang,
  • Zhao Wang,
  • Yang Sun,
  • Pengling Ge

摘要

Hepatocellular carcinoma (HCC), often arising from liver fibrosis in nonalcoholic fatty liver disease (NAFLD), remains a leading cause of cancer-related death. Targeting the gut–liver axis offers new therapeutic opportunities to prevent this progression. In this study, colon-targeted chitosan/pectin-based nanoparticles loaded with Astragalus polysaccharide (APs-CS/PT-NPs) were developed to modulate gut microbiota and inhibit liver tumorigenesis. The nanoparticles exhibited robust physicochemical stability and pH-responsive release. In vivo, oral administration of APs-CS/PT-NPs attenuated hepatic steatosis, reduced inflammatory cytokines, and suppressed NAFLD-induced HCC development. 16 S rRNA sequencing revealed restoration of microbial diversity and enhanced production of short-chain fatty acids, especially acetate. Mechanistically, transcriptomic profiling and functional analysis identified acetate as a key mediator, acting via G-protein-coupled receptor 43 (GPR43) to inhibit the NF-κB pathway. These results highlight the therapeutic potential of APs-CS/PT-NPs in modulating the gut–liver axis, rebalancing intestinal microbiota, and suppressing pro-inflammatory signaling. This nanoparticle-based strategy offers a promising food-derived preventive intervention for liver fibrosis–HCC transition.

Graphical Abstract