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Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis

Acta Pharmacologica Sinica volume 44, pages 1217–1226 (2023)Cite this article

Abstract

Retinoic-acid-receptor-related orphan receptor γ (RORγ) is a major transcription factor for proinflammatory IL-17A production. Here, we revealed that the RORγ deficiency protects mice from STZ-induced Type 1 diabetes (T1D) through inhibiting IL-17A production, leading to improved pancreatic islet β cell function, thereby uncovering a potential novel therapeutic target for treating T1D. We further identified a novel RORγ inverse agonist, ginseng-derived panaxadiol, which selectively inhibits RORγ transcriptional activity with a distinct cofactor recruitment profile from known RORγ ligands. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for panaxadiol in the RORγ ligand-binding pocket. Despite its inverse agonist activity, panaxadiol induced the C-terminal AF-2 helix of RORγ to adopt a canonical active conformation. Interestingly, panaxadiol ameliorates mice from STZ-induced T1D through inhibiting IL-17A production in a RORγ-dependent manner. This study demonstrates a novel regulatory function of RORγ with linkage of the IL-17A pathway in pancreatic β cells, and provides a valuable molecule for further investigating RORγ functions in treating T1D.

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Fig. 1: RORγ deficiency protects mice from STZ-induced type 1 diabetes.
Fig. 2: Identification of Ginseng-derived panaxadiol as a unique RORγ inverse agonist.
Fig. 3: Molecular recognition of panaxadiol by RORγ.
Fig. 4: Structural comparison of the RORγ-panaxadiol complex with RORγ-UA.
Fig. 5: The structural determinants of the interactions of RORγ with panaxadiol.
Fig. 6: Panaxadiol decreases IL-17A expression and production.
Fig. 7: Panaxadiol alleviates STZ-induced type 1 diabetes in mice.

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Data availability

The structure of RORγ/panaxadiol/SRC2 ternary complex was deposited to the Protein Data Bank with PDB ID of 7W3P.

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Acknowledgements

We thank the staff at BL19U1 of the Shanghai Synchrotron Radiation Source for assistance in data collection. This work was supported by grants from the National Natural Science Foundation of China (31770814).

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  1. These authors contributed equally: Si-yu Tian, Shu-ming Chen.

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  1. The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, China

    Si-yu Tian, Shu-ming Chen, Yong-yi Feng, Jia-ling He & Yong Li

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Contributions

SYT, SMC, YYF and JLH conducted the experiments. SYT contributed to the experiment design, performed structural analysis and wrote the manuscript. YYF contributed in editing the manuscript. YL designed the experiment and revised the manuscript.

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Correspondence to Yong Li.

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Tian, Sy., Chen, Sm., Feng, Yy. et al. Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis. Acta Pharmacol Sin 44, 1217–1226 (2023). https://doi.org/10.1038/s41401-022-01042-x

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