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A Vakognavine-Type Diterpenoid Alkaloid as FoxO1 Inhibitors against Rheumatoid Arthritis
Rongrong Zhang1,2, Xuechun Yu1, Siyuan Du1
1State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
Journal of the American Chemical Society
|June 26, 2026
Summary
A novel compound, delphyuanine A, from Delphinium yuanum Chen, shows potent antiarthritic effects by targeting the transcription factor FoxO1. This discovery offers a promising new avenue for treating rheumatoid arthritis and other autoimmune diseases.
Area of Science:
- Natural Product Chemistry
- Immunology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) is a systemic autoimmune disorder with significant unmet clinical needs.
- Current treatments often lack efficacy or have undesirable toxicity profiles.
- Developing novel, well-tolerated therapeutic agents for RA is crucial.
Purpose of the Study:
- To isolate and characterize C20-diterpenoid alkaloids from Delphinium yuanum Chen.
- To evaluate the anti-inflammatory and antiarthritic potential of isolated compounds.
- To elucidate the molecular mechanism of action for promising compounds.
Main Methods:
- Isolation and structural elucidation of 15 C20-diterpenoid alkaloids, including nine novel compounds (delphyuanines A-I).
- Assessment of nitric oxide inhibition in LPS-induced macrophage inflammation models.
- Evaluation of antiarthritic efficacy in an adjuvant-induced arthritis rat model.
- Identification of molecular targets using probe-affinity labeling assays and mechanistic studies.
Main Results:
- Nine novel compounds, delphyuanines A-I (1-9), were isolated from Delphinium yuanum Chen.
- Delphyuanine A (1), a rare vakognavine-type alkaloid, significantly inhibited nitric oxide production.
- Compound 1 demonstrated potent antiarthritic efficacy in vivo and directly targeted the transcription factor FoxO1.
- Mechanistic studies revealed that Compound 1 inhibits FoxO1 nuclear translocation, promotes M2 macrophage polarization, and suppresses the NF-κB pathway.
Conclusions:
- Delphyuanine A (1) exhibits significant anti-rheumatoid arthritis activity through direct targeting of FoxO1.
- The compound's mechanism involves modulating inflammatory pathways and macrophage polarization.
- Delphyuanine A represents a promising lead compound for developing novel anti-RA therapies and treating autoimmune diseases.
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