Synergistic mechanism of Shengyang Shiyiwei Pill in enhancing bevacizumab efficacy for hepatocellular carcinoma-associated ascites.

BACKGROUND: Hepatocellular carcinoma (HCC)-associated ascites remain a therapeutic challenge, with bevacizumab showing limited efficacy due to resistance. Shengyang Shiyiwei Pill (SYP), a traditional Chinese medicine, may offer a multi-targeted approach, but its synergistic mechanisms with bevacizumab require investigation. METHODS: In an H22-induced ascites model, we assessed SYP-bevacizumab combination therapy by measuring survival, ascites volume, and molecular markers (VEGFA, CD31, Caspase-3). HepG2 cells were treated with SYP-containing serum to evaluate cell cycle arrest and ferroptosis (GPX4, iron levels). Network pharmacology identified SYP's bioactive compounds and potential targets, followed by bioinformatics validation (TNMplot, HCCDB) and molecular docking analysis. RESULTS: The SYP-bevacizumab combination significantly reduced ascites volume and prolonged survival. Mechanistically, it downregulated VEGFA/CD31 while upregulating Caspase-3. SYP induced G0/G1-S phase-arrest and ferroptosis in HepG2 cells. Network pharmacology revealed quercetin and kaempferol as key active components targeting G6PD, with molecular docking confirming strong binding interactions. Bioinformatics analysis demonstrated that high G6PD expression correlated with poor HCC prognosis and immune cell infiltration. SYP restored sorafenib sensitivity in resistant cells through G6PD inhibition. CONCLUSION: SYP enhances bevacizumab efficacy by targeting angiogenesis, ferroptosis, and G6PD-mediated resistance, providing a rationale for integrating traditional and modern therapies in HCC management. These findings highlight the value of network pharmacology in elucidating TCM mechanisms and support further clinical evaluation.