Targeting Hepatocellular Carcinoma: Schisandrin A Triggers Mitochondrial Disruption and Ferroptosis

• Published in: Chemical biology & drug design 2024-12, Vol.104 (6), p.e70010
• Main Authors: He, Lin-Wei, Lin, Chang-Jie, Zhuang, Lin-Jun, Sun, Yi-Hui, Li, Ye-Cheng, Ye, Zhen-Yu
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Apoptosis - drug effects; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Cyclooctanes - chemistry; Cyclooctanes - pharmacology; Ferroptosis - drug effects; Humans; Lignans - chemistry; Lignans - pharmacology; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Polycyclic Compounds - chemistry; Polycyclic Compounds - pharmacology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.70010

The main focus of this research was to examine SchA's role in the hepatocellular carcinoma (HCC) development. LO2 and Huh7 cell viability were assessed using the MTT assay. The experiments included flow cytometry, colony formation, transwell, wound healing, and immunofluorescence assays to evaluate apoptosis levels, cells colony-forming ability, ROS levels, invasion and migration ability, and mitochondrial membrane potential. Biochemical kits was utilized for checking the ATP, mitochondrial DNA, MDA, GSH, and Fe levels in the Huh7 cells, and western blot for measuring the ferroptosis and AMPK/mTOR related-protein expression levels. The MTT assay demonstrated that SchA significantly reduced the vitality of Huh7 cells ranging from 10 to 50 μM, whereas it exhibited no discernible impact on LO2 cells. Additionally, SchA significantly inhibited colony-forming ability, invasion ability, and migration ability within the concentration range of 10 to 50 μM, with a reduction of 68% in colony formation at 50 μM. SchA also induced apoptosis in a dose-dependent manner. Moreover, SchA was observed to significantly elevate ROS levels dose-dependently, down-regulate mitochondrial membrane potential (JC-1) at 20 and 50 μM, and reduce the levels of ATP and mtDNA dose-dependently. Various concentrations of SchA resulted in a notable elevation in MDA and Fe levels as well as ACSL4 protein expression, accompanied by a reduction in GSH level and the protein expression of GPX4 and SLC7A11. Furthermore, SchA induced the activation of the AMPK/mTOR pathway in Huh7 cells, as evidenced by the increased phosphorylation level of AMPK and decreased phosphorylation level of mTOR. SchA might inhibit the progress of HCC through mitochondrial ferroptosis and dysfunction mediated by AMPK/mTOR pathway.