Neochlorogenic acid anchors MCU-based calcium overload for cancer therapy

Cancer is a major threat to human health worldwide, yet the clinical therapies remain unsatisfactory. In this study, we found that a Tetrastigma hemsleyanum leaves flavone (TLF) intervention could achieve tumor inhibition. Besides, neochlorogenic acid (NA), which had the highest absorbance peak in the HPLC profile of TLF, showed superior anti-proliferation ability over TLF, and could effectively trigger apoptosis, restrain migration, and facilitate cytoskeleton collapse, suggesting its key role in TLF's anticancer property. Molecular docking analysis suggested that NA was capable of binding with mitochondrial Ca2+ uniporter (MCU), and further experiments confirmed that NA upregulated the MCU level to permit excess calcium ion influx, leading to mitochondrial calcium imbalance, dysfunction, structure alteration, and ROS elevation. Moreover, tumor-bearing mice were applied to further confirm the excellent tumor inhibition ability of NA under Ca2+-abundant conditions. Therefore, this study uncovered that NA could effectively trigger robust MCU-mediated calcium overload cancer therapy, which could be utilized in novel strategies for future cancer treatment.