Solamargine Induces Hepatocellular Carcinoma Cell Apoptosis and Ferroptosis via Regulating STAT1/MTCH1 Axis

Background: Solamargine (SM) has been shown to play anti-tumor role in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of SM in HCC progression deserve further exploration. Methods: HCC cell proliferation and apoptosis were assessed by cell counting kit 8 assay, colony formation assay and flow cytometry. Ferroptosis was evaluated by detecting the levels of Fe2+, iron, MDA, ROS and GSH in HCC cells. In addition, mitochondrial carrier 1 (MTCH1) mRNA level was detected by quantitative real-time PCR. Western blot was used to test MTCH1 and signal transduction and activation of transcription 1 (STAT1) protein levels. Dual-luciferase reporter assay was employed to analyze the interaction between STAT1 and MTCH1. A mouse xenograft model was also constructed to explore the role of SM in vivo. Results: SM could potentially suppress HCC cell growth by inducing ferroptosis. MTCH1 was highly expressed in HCC tissues and cells, and its silencing inhibited HCC cell proliferation, promoted apoptosis and ferroptosis. MTCH1 expression was reduced by SM, and its overexpression reversed SM-induced HCC cell apoptosis and ferroptosis. Furthermore, STAT1 facilitated MTCH1 transcription and promoted its expression. Besides, STAT1 expression could be reduced by SM, and its overexpression abolished the decreasing effect of SM on MTCH1 expression. In vivo, SM suppressed HCC tumor growth by reducing MTCH1 expression. Conclusion: SM promoted HCC cell apoptosis and ferroptosis via the STAT1/MTCH1 axis. SM induces HCC cell apoptosis and ferroptosis;MTCH1 knockdown accelerates HCC cell apoptosis and ferroptosis;Transcription factor STAT1 promotes MTCH1 transcription;SM reduces MTCH1 expression by decreasing STAT1.