Shiyiwei Shenqi Pian-derived quercetin reactivates apoptosis in clear cell renal cell carcinoma by destabilizing survivin and x-linked inhibitor of apoptosis protein
Abstract
BACKGROUND
Clear cell renal cell carcinoma (ccRCC) strongly resists apoptosis via baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) and X-linked inhibitor of apoptosis protein (XIAP). Meanwhile, the specific anti-ccRCC mechanisms of the pro-apoptotic herbal mixture Shiyiwei Shenqi Pian (SSP) remain undefined.
PURPOSE
To systematically discover the key bioactive compound within SSP and characterize its precise mechanism of action in uncoupling the oncogenic BIRC5-XIAP complex.
STUDY DESIGN
An advanced integrative strategy combining network pharmacology, transcriptomic profiling, machine-learning, and structural dynamic simulations was utilized to screen and predict therapeutic targets. The in silico findings were then rigorously and sequentially validated across multiple experimental platforms, progressing from in vitro cell models to in vivo CDX and PDX settings.
METHODS
A multi-omics framework was applied to investigate the mechanisms of SSP in ccRCC. Active compounds and disease-related targets were identified through database mining and UPLC-Q-TOF-MS profiling, followed by machine-learning-based prioritization. Molecular interactions were analyzed using docking, molecular dynamics simulations, and single-cell transcriptomics. Protein interactions and stability were validated by co-immunoprecipitation (Co-IP), microscale thermophoresis (MST), cycloheximide (CHX)-chase, and ubiquitination assays. Cellular effects were assessed by proliferation and apoptosis…
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