Licochalcone A induces ROS-mediated apoptosis in colorectal cancer by targeting thioredoxin reductase-1

Colorectal cancer, a common malignant tumor of the digestive tract in clinical practice, poses substantial challenges to global public health. Licochalcone A (LicA), a flavonoid compound with antitumor activity extracted from Glycyrrhiza glabra L., has shown potential efficacy against colorectal cancer; however, its underlying mechanisms remain unclear. Initially, network pharmacology analysis identified associations between LicA and colorectal cancer and predicted potentially relevant signaling pathways. Thioredoxin reductase-1 (TrxR1), an antioxidant enzyme with peroxidase activity, is increasingly recognized as a promising target for anticancer therapy. We found that LicA directly targets TrxR1 to induce apoptosis in colorectal cancer cells by inhibiting TrxR1 activity and promoting reactive oxygen species (ROS) generation. Our data further emphasize that ROS is a critical mediator of LicA-induced apoptosis: excessive ROS accumulation causes mitochondrial oxidative stress damage. Additionally, LicA suppresses the growth of colorectal cancer xenografts in mice. These findings provide a foundation for the clinical application of LicA and offer a direction for developing TrxR1-targeted small-molecule drugs for colorectal cancer treatment.