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Screening the Mechanism of Shikonin Against Renal Cell Carcinoma via Network Pharmacology, Molecular Docking, and
Wen-Wei Gong1, Yue Yang2, Shi-Ming Wang2
1The First Clinical Medical College, Guizhou University of Traditional Chinese Medicine.
Abstract:
Renal cell carcinoma (RCC) is one of the most common tumors in the urinary system and has the highest mortality rate. Previous investigations have demonstrated that shikonin can treat renal cell carcinoma, but the mechanism remains unclear. Therefore, our study aimed to elucidate the mechanism of shikonin in the treatment of renal cell carcinoma using network pharmacology, molecular docking, and in vitro functional assays, including cell proliferation, migration, and apoptosis, with western blot (WB) validation. Shikonin targets were screened using PharmMapper, SwissTargetPrediction, and other databases, and identified RCC-related targets from Online Mendelian Inheritance in Man (OMIM), GeneCards, and other databases; the potential therapeutic targets were obtained by intersection analysis. A protein-protein interaction (PPI) network was constructed, and Cytoscape was used to screen core targets, while molecular docking was applied to analyze the binding affinity between shikonin and key targets. A total of 374 shikonin targets and 1,087 RCC-related targets were collected, and 98 overlapping target genes were identified. Six core targets (SRC, PIK3CA, PIK3CB, PIK3CD, PTPN11, and PIK3R1) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that shikonin exerted anti-RCC effects mainly by regulating protein kinase activity, HIF-1, and IL-17 signaling pathways. Molecular docking confirmed that shikonin had a strong binding affinity with these core targets. In vitro studies using human RCC Caki‑1 and 786‑O cells demonstrated that shikonin significantly inhibited cell proliferation and migration in a dose‑dependent manner, promoted cell apoptosis, and upregulated caspase‑3 and caspase‑8 activities. Western blot experiments further verified that shikonin modulated the expression of core target proteins and suppressed the HIF-1 signaling pathway. This study systematically elucidates the pharmacological mechanism of shikonin against renal cell carcinoma, providing a theoretical basis for the development and application of shikonin as a novel anti-RCC agent.
Insights
Shikonin effectively treats renal cell carcinoma (RCC) by inhibiting proliferation and migration while promoting apoptosis. This study elucidates its mechanism via network pharmacology and in vitro assays, identifying key targets and pathways.
Area of Science:
- Pharmacology
- Oncology
- Computational Biology
Background:
- Renal cell carcinoma (RCC) is a prevalent and lethal urinary system tumor.
- The therapeutic mechanism of shikonin against RCC requires elucidation.
Purpose of the Study:
- To elucidate the pharmacological mechanism of shikonin in treating renal cell carcinoma (RCC).
- To validate shikonin's efficacy using network pharmacology, molecular docking, and in vitro assays.
Main Methods:
- Screened shikonin and RCC targets using multiple databases (PharmMapper, OMIM, GeneCards).
- Constructed protein-protein interaction (PPI) network and identified core targets (SRC, PIK3CA, PIK3CB, PIK3CD, PTPN11, PIK3R1).
- Performed molecular docking, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses; conducted in vitro assays (proliferation, migration, apoptosis) and Western blot.
Main Results:
- Identified 98 overlapping targets between shikonin and RCC, with six core targets.
- Shikonin regulates protein kinase activity, HIF-1, and IL-17 signaling pathways.
- In vitro assays confirmed shikonin inhibits RCC cell proliferation and migration, induces apoptosis, and modulates core target protein expression.
Conclusions:
- Shikonin demonstrates significant anti-RCC activity through multifaceted molecular mechanisms.
- The study provides a theoretical foundation for developing shikonin as a novel anti-RCC therapeutic agent.
