Rehmannia glutinosa extract inhibits Henoch-Schönlein Purpura (IgA Vasculitis) by restoring regulatory T cell and T helper 17 cell balance via the PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Therapeutic choices remain limited for Henoch-Schönlein purpura (HSP), an IgA-associated vasculitis. Rehmannia glutinosa, a medicinal and edible herb traditionally used to "clear heat and cool blood," shows clinical promise, yet its precise pathogenesis remains elusive. PURPOSE: This study was designed to examine the therapeutic impact of Rehmannia glutinosa extract (RGE) on HSP, characterize its primary active components, and explore the mechanistic basis of its activity. STUDY DESIGN: An integrative approach encompassing in vivo and in vitro HSP models, network pharmacology, LC-MS, molecular docking, dynamics simulations, microbiomics, and metabolomics was utilized to systematically identify the anti-HSP material basis and underlying mechanisms of RGE. METHODS: Forty-one active components in RGE were identified via LC-MS. A multi-level computational strategy-encompassing network pharmacology, docking studies, and molecular dynamics was applied to screen and identify Catalpol (Cat) as the key active candidate. ICR mouse HSP models and cell cultures were treated with RGE or Cat. Pathological injuries, IgA deposition, and immune cell proportion changes were evaluated using RT-qPCR, Western blot, flow cytometry, and multiplex immunofluorescence. Furthermore, microbiomics and metabolomics were utilized to decipher the mechanism by which RGE exerts its effects through gut microbiota regulation. RESULTS: RGE and Cat significantly alleviated skin and kidney injuries and reduced abnormal IgA deposition. By suppressing the PI3K-AKT-mTOR/NF-κB pathway, they successfully rectified the Treg/Th17 imbalance and mitigated inflammatory cytokine production. Additionally, RGE effectively reshaped the gut microbiota ecology and regulated the metabolome. Molecular simulations further confirmed Cat as a key active compound. CONCLUSION: RGE exerts therapeutic effects on HSP through multi-target immunomodulation and gut microbiota remodeling, with Cat identified as a critical active component. These data support the herapeutic prospects of RGE and Cat in the prophylaxis and management of HSP.