Abstract
PURPOSE: Systemic lupus erythematosus (SLE) features immune cell dysfunction, causing immune - complex and inflammatory - factor formation that damages organs. Astragaloside IV (AS-IV), a cyclic triterpene saponin from Astragalus membranaceus, has strong anti-inflammatory and immunomodulatory effects. This study aimed to evaluate AS-IV's therapeutic potential for SLE and uncover its mechanism. METHODS: MRL/lpr mice were divided into MRL/lpr, low - medium - high - dose AS-IV, and Pred groups, with C57BL/6 mice as controls. Renal damage was assessed by histopathology and electron microscopy. Immune parameters were analyzed using ELISA, flow cytometry, immunofluorescence, and immunohistochemistry. Network pharmacology was used to find AS-IV's SLE targets, and molecular docking was employed to clarify its mechanism, with multiple methods used to measure target expression. RESULTS: AS-IV ameliorated renal pathology by reducing glomerular and vascular wall lesion scores while attenuating immune complex deposition. It significantly decreased podocyte foot process fusion rates, alleviated overall renal damage, and reduced key renal inflammatory cytokines. Systemically, AS-IV reduced spleen index and lowered anti-dsDNA, IgG levels, while restoring complement components C3 and C4, akin to the effects observed in the Pred group. AS-IV notably downregulated the expression of ITGB1, PTK2, p38, IL-4, IL-21, IL-17, and the Th1/Th2 and Th17 ratios, while upregulating the Treg ratio compared to the MRL/lpr group. Molecular docking and Western blot analyses further validated the interaction between AS-IV and the ITGB1/PTK2/p38 axis. CONCLUSION: AS-IV can modulate the ITGB1/PTK2/p38 axis to suppress immune inflammatory responses, thereby ameliorating SLE progression. These findings suggest the certain therapeutic value of AS-IV in managing SLE.