A multi-omic analysis reveals that Gamabufotalin exerts anti-hepatocellular carcinoma effects by regulating amino acid metabolism through targeting STAMBPL1

Abstract

BackgroundHepatocellular carcinoma (HCC), a prevalent type of liver cancer, is characterized by an unfavorable prognosis and a high mortality rate. Identifying novel treatments to prevent HCC recurrence and metastasis remains crucial for improving patient survival. Gamabufotalin (CS-6), a primary bufadienolide derived from the traditional Chinese medicine Chansu, has demonstrated significant anti-tumor activity. However, the effects and underlying mechanisms of CS-6 on HCC cells are not yet fully understood. PurposeThis study sought to elucidate the anti-HCC effects and potential mechanisms of CS-6. In vitro experiments were conducted using the HCC cell lines MHCC97H and Huh-7, employing CCK-8 assays, colony formation assays, wound healing assays, transwell invasion and migration assays, and flow cytometry to assess apoptosis and cell cycle dynamics. A multi-omics approach, including metabolomics and RNA sequencing analysis, was utilized to identify CS-6′s molecular targets and mechanisms in HCC therapy. Additionally, in vivo assessments were performed using xenografts in nude mice. ResultsCS-6 significantly inhibited HCC cell proliferation, migration, and invasion. Multi-omics analysis suggested that CS-6′s anti-HCC effects may involve the modulation of metabolic pathways, potentially through the downregulation of STAMBPL1, resulting in reduced mTOR signaling, increased apoptosis, and suppression of malignant HCC behavior. In vivo studies further confirmed that CS-6 significantly suppressed tumor growth and enhanced apoptosis and autophagy within tumors. ConclusionThese results underscore the therapeutic potential of CS-6 in HCC treatment. The study offers novel insights into the mechanism of CS-6, suggesting that its therapeutic efficacy may be uniquely mediated by targeting STAMBPL1. This distinct mechanism sets CS-6 apart from existing HCC treatments and positions it as a promising candidate for further clinical investigation.