Astragaloside IV ameliorates experimental autoimmune myasthenia gravis through multi-target regulation of immune-microbiota-metabolism network and ferroptosis inhibition.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder targeting neuromuscular junction proteins, with rising incidence and limited therapies. Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, exhibits immunomodulatory properties, but its mechanisms in MG remain unclear.

METHODS: We investigated the therapeutic efficacy and underlying mechanisms of AS-IV in an experimental autoimmune myasthenia gravis (EAMG) rat model using an integrated multi-omics approach, including 16S rRNA sequencing, metabolomics, and network pharmacology. Immune cell subsets (Th1, Th17, Treg, Tfh), gut microbiota, metabolic profiles, and ferroptosis-related pathways were analyzed.

RESULTS: AS-IV treatment significantly alleviated disease severity in EAMG rats by restoring immune homeostasis, evidenced by reduced pro-inflammatory Th1 and Th17 cells, increased regulatory T cells (Tregs), and suppressed T follicular helper (Tfh) cell responses. 16S rRNA sequencing revealed that AS-IV modulated gut microbiota composition, enriching beneficial taxa (Lactobacillus, Duncaniella) while suppressing pathogenic genera (Enterococcus_B). Metabolomic analysis identified AS-IV-mediated correction of metabolic disturbances, particularly in arachidonic acid metabolism pathways. Integrated network pharmacology and molecular docking analyses further identified the regulation of ferroptosis as a potential key mechanism, suggesting that AS-IV may exert its protective effects through inhibition of ferroptosis in EAMG.

CONCLUSION: AS-IV ameliorates EAMG through multi-target effects involving immune regulation, gut microbiota remodeling, metabolic reprogramming, and the inhibition of ferroptosis, highlighting its potential as a cost-effective adjunct therapy for MG.