Triptolide and quercetin coordinately regulate the network pharmacology mechanism of renal cancer

Renal cell carcinoma (RCC) is characterized by high metastatic potential, therapeutic resistance, and limited treatment options. Traditional Chinese Medicine (TCM)–derived compounds, such as triptolide and quercetin, possess anti-proliferative, pro-apoptotic, and anti-inflammatory activities, but their synergistic mechanisms against RCC remain unclear. A network pharmacology approach was employed to identify triptolide- and quercetin-related targets from TCMSP, PharmMapper, SwissTargetPrediction, and DrugBank. RCC-related targets were collected from GeneCards and OMIM. Common targets were visualized via Venny, and protein–protein interaction (PPI) networks were constructed using STRING and Cytoscape. Core targets were identified with six CytoNCA topology algorithms. In vitro validation was conducted using A498 cells, which were treated with triptolide (400 nM), quercetin (30 μM), or a combination of both for 48 h. Gene expression, protein levels, and cell viability were respectively measured using qRT-PCR, Western blot, and Bliss independence model-based synergy analysis. A total of 49 common targets for triptolide, quercetin, and RCC were identified, with 18 core genes linked to apoptosis, inflammation, and proliferation. GO/KEGG analyses revealed enrichment in TGF-β signaling, TNF signaling, cytokine–cytokine receptor interaction, and apoptosis pathways. Molecular docking showed strong binding of triptolide (−7.9 kcal/mol) and quercetin (−7.4 kcal/mol) to TGFB1. In A498 cells, combination therapy significantly downregulated BCL2, MAPK8, p-AKT, and TGFB1, upregulated TP53, TNF-α, and IL-6, and inhibited viability more than monotherapies (combination index = 0.75, P < 0.05), indicating synergism. Triptolide and quercetin synergistically suppress RCC cell survival via multi-target mechanisms involving TGF-β signaling inhibition, apoptosis induction, and inflammatory modulation. These findings support TCM-based combination strategies as potential complementary treatments for RCC, warranting further preclinical and clinical validation.