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<p>Naturally derived selective glucocorticoid receptor (GR) modulators dissociate anti-inflammatory efficacy from adverse effects. Rare ginsenosides have emerged as promising candidates for this selective modulation. This study explored rare ginsenosides derived from ginseng fibrous roots to evaluate their ability to selectively influence GR signaling. Rare ginsenosides were prepared from ginseng fibrous roots via alcoholic extraction, followed by targeted acid hydrolysis. Selective GR modulators were screened using a combination of molecular docking, molecular dynamics simulation, and cellular assays. The selective regulation of GR signaling was further validated in a DSS-induced murine colitis model using dexamethasone (DEX) as a positive control. Four rare ginsenosides, 20(<i>R</i>)-Rg3, 20(<i>S</i>)-Rg3, Rk1, and Rg5, were obtained. Computational analyses revealed that 20(<i>R</i>)-Rg3 bound strongly and stably to GR. In cellular models, 20(<i>R</i>)-Rg3 promoted GR nuclear translocation and suppressed inflammatory responses by reducing NO, IL-6 and TNF-α production. Notably, 20(<i>R</i>)-Rg3 selectively induced GR-mediated transrepression by inhibiting NF-κBRE-dependent transcription without activating GRE-driven transactivation, identifying it as a functionally selective GR modulator. In vivo oral administration of 20(<i>R</i>)-Rg3 significantly alleviated colonic inflammation, as evidenced by clinical signs, colon histopathology, serum TNF-α and IL-6 levels, together with colonic MPO activity and phosphorylated levels of NF-κB p65 and IκBα. High-dose 20(<i>R</i>)-Rg3 exhibited efficacy comparable to that of dexamethasone while preserving thymus and spleen integrity and avoiding the induction of GR transactivation-associated metabolic genes (TAT and PEPCK). These results demonstrate that 20(<i>R</i>)-Rg3, derived from ginseng fibrous roots, functions as a natural selective GR modulator with anti-inflammatory activity. Its ability to dissociate therapeutic efficacy from systemic side effects highlights its potential as a safer alternative to conventional corticosteroids in management of inflammatory diseases.</p>

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20(R)-Rg3 derived from ginseng fibrous roots ameliorates DSS-induced colitis via selective modulation of glucocorticoid receptor signaling

  • 期刊论文

  • 发表日期：

    2026年5月1日

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  • Xinyu Kong,
  • Pei Wang,
  • Shumin Zhang,
  • Lijuan Kou,
  • Mengxia Tan,
  • Zeping Xie,
  • Wei Guo

摘要

Naturally derived selective glucocorticoid receptor (GR) modulators dissociate anti-inflammatory efficacy from adverse effects. Rare ginsenosides have emerged as promising candidates for this selective modulation. This study explored rare ginsenosides derived from ginseng fibrous roots to evaluate their ability to selectively influence GR signaling. Rare ginsenosides were prepared from ginseng fibrous roots via alcoholic extraction, followed by targeted acid hydrolysis. Selective GR modulators were screened using a combination of molecular docking, molecular dynamics simulation, and cellular assays. The selective regulation of GR signaling was further validated in a DSS-induced murine colitis model using dexamethasone (DEX) as a positive control. Four rare ginsenosides, 20(R)-Rg3, 20(S)-Rg3, Rk1, and Rg5, were obtained. Computational analyses revealed that 20(R)-Rg3 bound strongly and stably to GR. In cellular models, 20(R)-Rg3 promoted GR nuclear translocation and suppressed inflammatory responses by reducing NO, IL-6 and TNF-α production. Notably, 20(R)-Rg3 selectively induced GR-mediated transrepression by inhibiting NF-κBRE-dependent transcription without activating GRE-driven transactivation, identifying it as a functionally selective GR modulator. In vivo oral administration of 20(R)-Rg3 significantly alleviated colonic inflammation, as evidenced by clinical signs, colon histopathology, serum TNF-α and IL-6 levels, together with colonic MPO activity and phosphorylated levels of NF-κB p65 and IκBα. High-dose 20(R)-Rg3 exhibited efficacy comparable to that of dexamethasone while preserving thymus and spleen integrity and avoiding the induction of GR transactivation-associated metabolic genes (TAT and PEPCK). These results demonstrate that 20(R)-Rg3, derived from ginseng fibrous roots, functions as a natural selective GR modulator with anti-inflammatory activity. Its ability to dissociate therapeutic efficacy from systemic side effects highlights its potential as a safer alternative to conventional corticosteroids in management of inflammatory diseases.