Quercetin, a Natural Dietary Flavonoid, Emerges a Novel USP7 Inhibitor with Anti-colorectal Cancer Effects

Abstract

The human deubiquitinating enzyme ubiquitin-specific peptidase 7 (USP7) has emerged as a promising anti-tumor target, particularly in colorectal cancer, due to its regulation of the MDM2/p53 axis. Through a combination of ubiquitin C-terminal 7-amido-4-methylcoumarin hydrolysis assay and ubiquitin-propargylamide protease profiling, we identified the natural dietary flavonoid quercetin as a potent USP7 inhibitor in both cell-free and cellular contexts. Cellular thermal shift and surface plasmon resonance analyses demonstrated that quercetin is directly bound to USP7. Consistent with USP7 target engagement in cells, quercetin decreased MDM2 levels and subsequently increased the levels of p53. Moreover, quercetin also suppressed colorectal cancer cell proliferation by inducing G2/M cell cycle arrest and inhibiting cell migration. Collectively, our study identified quercetin as a novel and effective USP7 inhibitor with potent anti-colorectal cancer activity, highlighting its therapeutic potential for targeting the USP7–MDM2–p53 axis and warranting further exploration as a promising therapeutic agent in colorectal cancer treatment.