A Vakognavine-Type Diterpenoid Alkaloid as FoxO1 Inhibitors against Rheumatoid Arthritis.

Rheumatoid arthritis is a systemic autoimmune disorder with a markedly unmet clinical need for highly effective and well-tolerated therapeutic agents with minimal toxicity. Herein, 15 C20-diterpenoid alkaloids, including nine novel compounds, delphyuanines A-I (1-9), were isolated from Delphinium yuanum Chen. Notably, delphyuanine A (1) represents an exceptionally rare vakognavine-type C20-diterpenoid alkaloid with only 22 congeners of this subclass reported to date. Furthermore, in an LPS-induced macrophage inflammation model, nitric oxide production was substantially inhibited by Compound 1, and its inhibitory effect was markedly stronger than that of the other isolated compounds. Moreover, Compound 1 exhibits potent antiarthritic efficacy in an adjuvant-induced arthritis rat model. Using a probe-affinity labeling assay, the transcription factor FoxO1 was confirmed to be the direct molecular target of Compound 1. Further molecular mechanistic studies demonstrated that Compound 1 exerts antirheumatoid arthritis activity by directly targeting FoxO1, thereby inhibiting its nuclear translocation, promoting M2 macrophage polarization, and suppressing the NF-κB signaling pathway. Collectively, these findings provide valuable guidance for the rational design of anti-RA drugs and identifies Compound 1 as a promising lead compound for the treatment of autoimmune diseases.