Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway
BackgroundGinsenoside Re (G-Re), a unique ginsenoside almost exclusively found in Araliaceae plants, is a promising therapeutic agent for attenuating liver injury. This study aims to investigate the liver-protective effects of G-Re and the underlying mechanisms in acute liver injury models.MethodsMa...
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Frontiers Media S.A.
2025-06-01
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| author | Jing Lin Huan Wang Ruowei Zhao Shaohua Li Dennis Chang Yanfang Zheng Xian Zhou Rui Huang Mingqing Huang |
| author_facet | Jing Lin Huan Wang Ruowei Zhao Shaohua Li Dennis Chang Yanfang Zheng Xian Zhou Rui Huang Mingqing Huang |
| author_sort | Jing Lin |
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| description | BackgroundGinsenoside Re (G-Re), a unique ginsenoside almost exclusively found in Araliaceae plants, is a promising therapeutic agent for attenuating liver injury. This study aims to investigate the liver-protective effects of G-Re and the underlying mechanisms in acute liver injury models.MethodsMale C57BL/6 mice were intraperitoneally injected with various agents induce the acute liver injury model after pre-treatment with G-Re (5–20 mg/kg, oral gavage). Additionally, the phosphoinositide 3-kinases (PI3K) inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor RAPA were co-administered with G-Re in the thioacetamide (TAA)-induced rat hepatic stellate cell line (HSC-T6) to explore the mechanisms associated with G-Re.ResultsG-Re at (20 mg/kg) protected liver against thioacetamide (TAA), ethanol, acetaminophen, and D-Galactosamine-induced liver injury in C57BL/6 mice. G-Re reduced serum levels of aspartate aminotransferase (AST) from 151.98 to 40.24 U/L and alanine aminotransferase (ALT) from 392.04 to 49.43 U/L. Both in vivo and in vitro studies consistently showed that G-Re decreased mRNA expression levels of key pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Additionally, G-Re dose-dependently downregulated the protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), NOD-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase −1 (caspase-1), interleukin-18 (IL-18), and IL-1β. In addition, our results suggested that the suppression of autophagy by G-Re may play a crucial role in its ability to inhibit the NLRP3 inflammasome. Notably, this regulatory effect on autophagy appears to be mediated through the phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR signaling pathway). G-Re inhibits autophagy in both cellular and animal models by downregulating the expression of light chain 3-II (LC3-II), Beclin-1, and sequestosome-1 (p62) through this pathway. Furthermore, the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin (RAPA) were shown to partially reverse the inhibitory effects of G-Re on autophagy and inflammation in HSC-T6 cells. These results further support the notion that reactivation of autophagy can counteract G-Re–mediated suppression of NLRP3 and caspase-1 expression.ConclusionThis study highlights G-Re as a promising therapeutic candidate for liver injury, acting through inhibition of autophagy and inflammation via the PI3K/AKT/mTOR signaling pathway. |
| format | Article |
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| publishDate | 2025-06-01 |
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| spelling | doaj-art-f377b097f6d44cccb88c62d8078d7bff2025-08-20T03:47:20ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-06-011610.3389/fphar.2025.15922031592203Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathwayJing Lin0Huan Wang1Ruowei Zhao2Shaohua Li3Dennis Chang4Yanfang Zheng5Xian Zhou6Rui Huang7Mingqing Huang8The Affiliated People’s Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaThe Affiliated People’s Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaThe Affiliated People’s Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaThe Affiliated People’s Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaNICM Health Research Institute, Western Sydney University, Westmead, NSW, AustraliaThe Affiliated People’s Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaNICM Health Research Institute, Western Sydney University, Westmead, NSW, AustraliaDepartment of Nursing, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, ChinaThe Affiliated People’s Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaBackgroundGinsenoside Re (G-Re), a unique ginsenoside almost exclusively found in Araliaceae plants, is a promising therapeutic agent for attenuating liver injury. This study aims to investigate the liver-protective effects of G-Re and the underlying mechanisms in acute liver injury models.MethodsMale C57BL/6 mice were intraperitoneally injected with various agents induce the acute liver injury model after pre-treatment with G-Re (5–20 mg/kg, oral gavage). Additionally, the phosphoinositide 3-kinases (PI3K) inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor RAPA were co-administered with G-Re in the thioacetamide (TAA)-induced rat hepatic stellate cell line (HSC-T6) to explore the mechanisms associated with G-Re.ResultsG-Re at (20 mg/kg) protected liver against thioacetamide (TAA), ethanol, acetaminophen, and D-Galactosamine-induced liver injury in C57BL/6 mice. G-Re reduced serum levels of aspartate aminotransferase (AST) from 151.98 to 40.24 U/L and alanine aminotransferase (ALT) from 392.04 to 49.43 U/L. Both in vivo and in vitro studies consistently showed that G-Re decreased mRNA expression levels of key pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Additionally, G-Re dose-dependently downregulated the protein expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), NOD-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase −1 (caspase-1), interleukin-18 (IL-18), and IL-1β. In addition, our results suggested that the suppression of autophagy by G-Re may play a crucial role in its ability to inhibit the NLRP3 inflammasome. Notably, this regulatory effect on autophagy appears to be mediated through the phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR signaling pathway). G-Re inhibits autophagy in both cellular and animal models by downregulating the expression of light chain 3-II (LC3-II), Beclin-1, and sequestosome-1 (p62) through this pathway. Furthermore, the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin (RAPA) were shown to partially reverse the inhibitory effects of G-Re on autophagy and inflammation in HSC-T6 cells. These results further support the notion that reactivation of autophagy can counteract G-Re–mediated suppression of NLRP3 and caspase-1 expression.ConclusionThis study highlights G-Re as a promising therapeutic candidate for liver injury, acting through inhibition of autophagy and inflammation via the PI3K/AKT/mTOR signaling pathway.https://www.frontiersin.org/articles/10.3389/fphar.2025.1592203/fullginsenoside Reacute liver injuryPI3K/AKT/mTORautophagyNLRP3 inflammasomemale mice |
| spellingShingle | Jing Lin Huan Wang Ruowei Zhao Shaohua Li Dennis Chang Yanfang Zheng Xian Zhou Rui Huang Mingqing Huang Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway Frontiers in Pharmacology ginsenoside Re acute liver injury PI3K/AKT/mTOR autophagy NLRP3 inflammasome male mice |
| title | Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway |
| title_full | Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway |
| title_fullStr | Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway |
| title_full_unstemmed | Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway |
| title_short | Ginsenoside Re ameliorates thioacetamide-induced acute liver injury through inhibiting autophagy-NLRP3 inflammasome pathway |
| title_sort | ginsenoside re ameliorates thioacetamide induced acute liver injury through inhibiting autophagy nlrp3 inflammasome pathway |
| topic | ginsenoside Re acute liver injury PI3K/AKT/mTOR autophagy NLRP3 inflammasome male mice |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1592203/full |
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