Salidroside alleviates TNF-α-induced endothelial inflammatory injury by modulating NF-κB/NLRP3 inflammasome-related signaling: an integrated network pharmacology and experimental study

  • Transl Pediatr. 2026 Jun 30;15(6):237. doi: 10.21037/tp-2026-0388.
Jiahui Meng  #  1 ,  Weiwei Li  #  2 ,  Lan He  1 ,  Guoying Huang  1  3 ,  Fang Liu  1
Affiliations
  • 1. Heart Center, Children's Hospital of Fudan University, Shanghai, China.
  • 2. Institute of Pediatrics, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
  • 3. Shanghai Key Laboratory of Birth Defects, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
  • # Contributed equally.
PMID: 42433942 DOI: 10.21037/tp-2026-0388
Abstract

Background: Kawasaki disease (KD) is an acute febrile vasculitis in children, and vascular endothelial injury is a central event in the development of coronary artery lesions. Salidroside (SAL), a natural active compound extracted from Rhodiola rosea, has anti-inflammatory, anti-apoptotic, and immunomodulatory properties. However, its mechanism in KD-related vascular inflammatory injury remains unclear. This study aimed to investigate the protective effects and potential mechanisms of SAL in endothelial injury relevant to KD.

Methods: Potential targets of SAL were predicted using reverse virtual screening and SwissTargetPrediction. KD-related targets were collected from the GeneCards and DisGeNET databases. Overlapping targets were subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction analyses. Key targets were further evaluated by molecular docking. Human coronary artery endothelial cells (HCAECs) were stimulated with tumor necrosis factor-α (TNF-α) to establish an endothelial inflammatory injury model. RNA-sequencing (RNA-seq) was performed to identify differentially expressed genes after SAL treatment. The protective effects of SAL were then assessed by Cell Counting Kit-8 assay, wound-healing assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) flow cytometry, reverse transcription quantitative polymerase chain reaction, and western blotting.

Results: Network pharmacology identified 226 potential SAL targets and 2,686 KD-related targets, with 56 overlapping targets. KEGG enrichment and RNA-seq indicated that SAL may regulate a broader inflammatory network, particularly interleukin (IL)-17 and TNF signaling pathways. Molecular docking showed stable binding of SAL to matrix metalloproteinase-9 (MMP-9). In TNF-α-stimulated HCAECs, SAL significantly improved cell viability, inhibited excessive migration, and reduced inflammatory cell death. SAL also decreased the messenger RNA (mRNA) expression of IL-1β, IL-6, MMP-9, interleukin-17 receptor A (IL-17RA), intercellular adhesion molecule-1 (ICAM-1), and NOD-like Receptor family pyrin domain containing 3 (NLRP3), and reduced the protein levels of IL-6, phosphorylated nuclear factor kappa B (NF-κB) p65, NLRP3, gasdermin D (GSDMD), and Caspase-1 (P<0.05).

Conclusions: SAL alleviates TNF-α-induced endothelial inflammatory injury in HCAECs. Its protective effects are associated with suppression of inflammatory signaling, inhibition of abnormal migration and cell death, and attenuation of NF-κB/NLRP3 inflammasome-related molecules. These findings provide preliminary experimental evidence for further investigation of SAL in KD-related vascular inflammation.

Keywords
Kawasaki disease (KD); NOD-like receptor family pyrin domain containing 3 (NLRP3); network pharmacology; nuclear factor kappa B (NF-κB); salidroside (SAL).
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