Chinese Medicine (United Kingdom) · Published 2026-07-29 · DOI 10.1186/s13020-026-01476-z
Ping Tang, Guibao Luo, Huihui Xue, Chunsheng Yang
Abstract Background Multiple sclerosis (MS) is a debilitating neuroinflammatory disease. Experimental autoimmune encephalomyelitis (EAE) is a commonly used rodent model for MS. Forsythoside A (FA), a natural compound derived from Forsythia suspensa, exhibits anti-inflammatory and neuroprotective properties; however, its efficacy in EAE and its underlying mechanism remain unclear. Purpose To explore the therapeutic effect of FA on EAE and its mechanism. Methods EAE was induced in C57BL/6 mice treated with FA (20/60 mg/kg) from day 7. Clinical scores, histopathology (H&E, LFB, immunofluorescence), flow cytometry, and spinal cord RNA sequencing were analyzed. Network pharmacology, molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) were employed to identify and validate the target of FA. In vitro studies using BV2 microglia with Tnfaip2 knockdown/overexpression confirmed the mechanism via qRT-PCR and Western blot. Results FA treatment dose-dependently alleviated clinical severity. While the 20 mg/kg dose showed a trend toward improvement without statistical significance, the 60 mg/kg dose significantly reduced CNS inflammation and demyelination. FA decreased peripheral Th1 cells in EAE mice. It suppressed microglial activation and pro-inflammatory markers (IL-1β, TNF-α, iNOS) expression. Transcriptomics and network analysis pinpointed TNF-α-induced protein 2 (Tnfaip2) in the TNF pathway. FA directly bound Tnfaip2 (KD = 28 µM), validated by docking, MD simulations, and SPR. In vitro, FA inhibited LPS-induced pro-inflammatory polarization and the Tnfaip2/NF-κB pathway in BV2 cells. Tnfaip2 overexpression abolished the anti-inflammatory effects of FA. Conclusion FA ameliorates EAE by suppressing pro-inflammatory microglial polarization via directly targeting Tnfaip2 and inhibiting the NF-κB pathway. This identifies the Tnfaip2/NF-κB axis as a potential therapeutic target for MS.
Abstract from DOAJ. Public domain (CC0 1.0).
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Tang, P., Luo, G., Xue, H., et al. (2026). Forsythoside A alleviates experimental autoimmune encephalomyelitis by targeting Tnfaip2. Chinese Medicine (United Kingdom). https://doi.org/10.1186/s13020-026-01476-z