Abstract

Background: The STING (Stimulator of Interferon Genes) pathway plays a pivotal role in regulating innate immune responses and chronic inflammation, with increasing evidence linking its dysregulation to neuroinflammatory and autoimmune disorders. While synthetic STING modulators have been widely studied, the therapeutic potential of plant-derived compounds remains largely untapped.

Objective: This study sought to evaluate and compare the inhibitory effects of three natural bioactive molecules—Baicalin, Nuciferine, and Tanshinone IIA—against the STING pathway, using the nonsteroidal anti-inflammatory drug (NSAID) Etodolac as a benchmark.

Methods: Molecular docking was performed using the optimized structure of STING (PDB ID: 6NT5) in AutoDock Vina through PyRx, with ligand optimization via PubChem, Open Babel, and AutoDock Tools. ADME properties and toxicity risks were predicted using SwissADME and ProTox-II. Functional enrichment and gene co-expression analyses were conducted using STRING-db, GeneMANIA, and Enrichr, while structural flexibility was examined through Normal Mode Analysis (NMA) on iMODS.

Results: Among the tested compounds, Tanshinone IIA displayed the strongest binding affinity, supported by stable π-interactions and excellent blood–brain barrier permeability. Co-expression and ontology analyses confirmed its close association with key immune signaling regulators (TBK1, IRF3, NFKB1). NMA further demonstrated high complex stability and adaptability, while toxicity predictions indicated a favorable safety profile.

Conclusion: Collectively, these findings highlight Tanshinone IIA as a promising natural STING inhibitor with potential applications in managing neuroinflammation. Further in vitro and in vivo validation is warranted to confirm its efficacy and safety in clinical contexts.

Keywords: STING pathway, Tanshinone IIA, neuroinflammation, molecular docking, natural bioactive compounds