Turn off MathJax
Article Contents
Lifan Lin, Xinmiao Li, Yifei Li, Zhichao Lang, Yeping Li, Jianjian Zheng. Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2023.11.009
Citation: Lifan Lin, Xinmiao Li, Yifei Li, Zhichao Lang, Yeping Li, Jianjian Zheng. Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2023.11.009

Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis

doi: 10.1016/j.jpha.2023.11.009

The project was supported by Wenzhou Municipal Science and technology Bureau, China (Grant No.: Y20220023), Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, China (Grant No.: 2022E10022), and the Project of Wenzhou Medical University Basic Scientific Research, China (Grant No.: KYYW201904).

  • Received Date: Aug. 29, 2023
  • Accepted Date: Nov. 21, 2023
  • Rev Recd Date: Nov. 02, 2023
  • Available Online: Nov. 30, 2023
  • Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), a process associated with ferroptosis. Ginsenoside Rb1 (GRb1), a major active component extracted from Panax ginseng, inhibits HSC activation. However, the potential role of GRb1 in mediating HSC ferroptosis remains unclear. This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro, using CCl4-induced liver fibrosis mouse model and primary HSCs, LX-2 cells. The findings revealed that GRb1 effectively inactivated HSCs in vitro, reducing alpha-smooth muscle actin and Type I collagen levels. Moreover, GRb1 significantly alleviated CCl4-induced liver fibrosis in vivo. From a mechanistic standpoint, the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1. Specifically, GRb1 promoted HSC ferroptosis both in vivo and in vitro, characterized by increased glutathione depletion, malondialdehyde production, iron overload, and accumulation of reactive oxygen species. Intriguingly, GRb1 increased Beclin 1 (BECN1) levels and decreased the System Xc-key subunit SLC7A11. Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1. Moreover, BECN1 could directly interact with SLC7A11, initiating HSC ferroptosis. In conclusion, the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro. Overall, this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation, at least partly through its modulation of BECN1 and SLC7A11.
  • loading
  • E. Devaraj, E. Perumal, R. Subramaniyan, et al., Liver fibrosis: Extracellular vesicles mediated intercellular communication in perisinusoidal space, Hepatology 76 (2022) 275-285.
    D. Karin, Y. Koyama, D. Brenner, et al., The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis, Differ. Res. Biol. Divers. 92 (2016) 84-92.
    A. Jangra, A. Kothari, P. Sarma, et al., Recent advancements in antifibrotic therapies for regression of liver fibrosis, Cells 11 (2022), 1500.
    L. Qin, N. Liu, C.-L.-M. Bao, et al., Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin, Acta Pharmacol. Sin. 44 (2023) 268-287.
    S.C. Koeberle, A.P. Kipp, H. Stuppner, et al., Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling, Med. Res. Rev. 43 (2023) 614-682.
    B.R. Stockwell, J.P.F. Angeli, H. Bayir, et al., Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease, Cell 171 (2017) 273-285.
    V. Otasevic, M. Vucetic, I. Grigorov, et al., Ferroptosis in different pathological contexts seen through the eyes of mitochondria, Oxid. Med. Cell. Longev. 2021 (2021), 5537330.
    F. Zeng, L. Ye, Q. Zhou, et al., Inhibiting SCD expression by IGF1R during lorlatinib therapy sensitizes melanoma to ferroptosis, Redox Biol. 61 (2023), 102653.
    P. Luo, D. Liu, Q. Zhang, et al., Celastrol induces ferroptosis in activated HSCs to ameliorate hepatic fibrosis via targeting peroxiredoxins and HO-1, Acta Pharm. Sin. B 12 (2022) 2300-2314.
    S. Huang, Y. Wang, S. Xie, et al., Isoliquiritigenin alleviates liver fibrosis through caveolin-1-mediated hepatic stellate cells ferroptosis in zebrafish and mice, Phytomed. 101 (2022), 154117.
    Q. Ruan, C. Wen, G. Jin, et al., Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity, Phytomed. 118 (2023), 154990.
    C. Chen, W. Gong, J. Tian, et al., Radix Paeoniae Alba attenuates Radix Bupleuri-induced hepatotoxicity by modulating gut microbiota to alleviate the inhibition of saikosaponins on glutathione synthetase, J. Pharm. Anal. 13 (2023) 640-659.
    W. Zha, Y. Sun, W. Gong, et al., Ginseng and ginsenosides: Therapeutic potential for sarcopenia, Biomedecine Pharmacother. 156 (2022), 113876.
    Z. Lin, R. Xie, C. Zhong, et al., Recent progress (2015-2020) in the investigation of the pharmacological effects and mechanisms of ginsenoside Rb1, a main active ingredient in Panax ginseng Meyer, J. Ginseng Res. 46 (2022) 39-53.
    Y. Ni, H. Deng, L. Zhou, et al., Ginsenoside Rb1 ameliorated bavachin-induced renal fibrosis via suppressing bip/eIF2α/CHOP signaling-mediated EMT, Front. Pharmacol. 13 (2022), 872474.
    R. Zhang, X. Li, Y. Gao, et al., Ginsenoside Rg1 epigenetically modulates Smad7 expression in liver fibrosis via microRNA-152, J. Ginseng Res. 47 (2023) 534-542.
    I. Mederacke, D.H. Dapito, S. Affo, et al., High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers, Nat. Protoc. 10 (2015) 305-315.
    J. Zhang, S. Chen, S. Wei, et al., CircRAPGEF5 interacts with RBFOX2 to confer ferroptosis resistance by modulating alternative splicing of TFRC in endometrial cancer, Redox Biol. 57 (2022), 102493.
    M. Shen, Y. Li, Y. Wang, et al., N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells, Redox Biol. 47 (2021), 102151.
    Y.-L. Hou, Y.-H. Tsai, Y.-H. Lin, et al., Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats, BMC Complementary Altern. Med. 14 (2014), 415.
    X. Song, S. Zhu, P. Chen, et al., AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system xc- activity, Curr. Biol. 28 (2018) 2388-2399.e5.
    S. Sharma, D. Le Guillou, J.Y. Chen, Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis, Nat. Rev. Gastroenterol. Hepatol. 20 (2023) 662-678.
    Q. Pei, Q. Yi, L. Tang, Liver fibrosis resolution: From molecular mechanisms to therapeutic opportunities, Int. J. Mol. Sci. 24 (2023), 9671.
    Q. Zhang, P. Luo, L. Zheng, et al., 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs, J. Pharm. Anal. 12 (2022) 570-582.
    S. Chen, J. Zhu, X. Zang, et al., The emerging role of ferroptosis in liver diseases, Front. Cell Dev. Biol. 9 (2021), 801365.
    K. Du, R. Maeso-Diaz, S.H. Oh, et al., Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis, Hepatology 77 (2023) 1998-2015.
    H. Gao, N. Kang, C. Hu, et al., Ginsenoside Rb1 exerts anti-inflammatory effects in vitro and in vivo by modulating toll-like receptor 4 dimerization and NF-kB/MAPKs signaling pathways, Phytomed. 69 (2020), 153197.
    N. Ni, Q. Liu, H. Ren, et al., Ginsenoside Rb1 protects rat neural progenitor cells against oxidative injury, Molecules 19 (2014) 3012-3024.
    J. Liu, G. Fan, N. Tao, et al., Ginsenoside Rb1 Alleviates Bleomycin-Induced Pulmonary Inflammation and Fibrosis by Suppressing Central Nucleotide-Binding Oligomerization-, Leucine-Rich Repeat-, and Pyrin Domains-Containing Protein Three Inflammasome Activation and the NF-κB Pathway, Drug Des. Devel. Ther. 16 (2022) 1793-1809.
    Y.-T. Lo, Y.-H. Tsai, S.-J. Wu, et al., Ginsenoside Rb1 inhibits cell activation and liver fibrosis in rat hepatic stellate cells, J. Med. Food 14 (2011) 1135-1143.
    J. Chen, X. Li, C. Ge, et al., The multifaceted role of ferroptosis in liver disease, Cell Death Differ. 29 (2022) 467-480.
    Z. Zhang, M. Guo, M. Shen, et al., The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells, Redox Biol. 36 (2020), 101619.
    A. Wu, B. Feng, J. Yu, et al., Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis, Redox Biol. 46 (2021), 102131.
    E. Wirawan, S. Lippens, T. Vanden Berghe, et al., Beclin1: A role in membrane dynamics and beyond, Autophagy 8 (2012) 6-17.
    F. Hu, G. Li, C. Huang, et al., The autophagy-independent role of BECN1 in colorectal cancer metastasis through regulating STAT3 signaling pathway activation, Cell Death Dis. 11 (2020), 304.
    R. Kang, S. Zhu, H.J. Zeh, et al., BECN1 is a new driver of ferroptosis, Autophagy 14 (2018) 2173-2175.
    Z. Yin, G. Ding, X. Chen, et al., Beclin1 haploinsufficiency rescues low ambient temperature-induced cardiac remodeling and contractile dysfunction through inhibition of ferroptosis and mitochondrial injury, Metab. 113 (2020), 154397.
    C. Huang, L. Chen, G. Chen, et al., SHP-1/STAT3-signaling-axis-regulated coupling between BECN1 and SLC7A11 contributes to sorafenib-induced ferroptosis in hepatocellular carcinoma, Int. J. Mol. Sci. 23 (2022), 11092.
    Y. Tan, Y. Huang, R. Mei, et al., HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis, Cell Death Dis. 13 (2022), 319.
    X. Chen, C. Yu, R. Kang, et al., Cellular degradation systems in ferroptosis, Cell Death Differ. 28 (2021) 1135-1148.
    Z. Lang, S. Yu, Y. Hu, et al., Ginsenoside Rh2 promotes hepatic stellate cell ferroptosis and inactivation via regulation of IRF1-inhibited SLC7A11, Phytomed. 118 (2023), 154950.
    K. Yan, T. Hou, L. Zhu, et al., PM2.5 inhibits system Xc- activity to induce ferroptosis by activating the AMPK-Beclin1 pathway in acute lung injury, Ecotoxicol. Environ. Saf. 245 (2022), 114083.
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (47) PDF downloads(4) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint