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

In this study, we report that Fresh Rehmannia glutinosa extract (RGE), effectively prevents and treats Henoch-Schönlein Purpura (HSP) by regulating the PI3K-AKT-mTOR signaling pathway to restore the Treg/Th17 balance. • RGE, a traditional "medicinal and edible homology" herb recently added to China's 2024 list, demonstrates therapeutic potential for HSP by aligning with the TCM principle of "clearing descending fire and nourishing yin" to treat blood syndromes. • RGE and its core active component catalpol significantly alleviate HSP symptoms, reducing skin and renal purpura, pathological damage, and IgA deposition in mouse models. • RGE and its core active component catalpol restore Treg/Th17 balance and suppresses inflammatory cytokines by inhibiting the PI3K-AKT-mTOR/NF-κB signaling pathway, as confirmed by network pharmacology, molecular docking, and in vivo/in vitro experiments. • Multi-omics analysis reveals that RGE intervention reshapes gut microbiota structure and regulates metabolic homeostasis, suggesting a protective "gut-microbiota-immune" mechanism in HSP treatment. 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. Download: Download high-res image (351KB) Download: Download full-size image