摘要：The dysregulation of pathways regulat-ing cellular function is a frequent hall-mark of cancer and the development of specific pathway inhibitors that alter tumor growth and progression are the focus of multiple recent studies. E3 ubiquitin ligases are a large group of diverse protein enzymes that specifically target proteins for dear- ance, and their importance to normal cel-lular function is illustrated in the many diseases associated with their loss of func- tion or inappropriate targeting. S-phase kinase-associated protein 2 （Skp2） is an F box protein that plays critical roles in cell-cycle progression, senescence, metabolism, and acts as an Skpl-Cullin-l-F box （SCF） ubiquitin ligase substrate recognition fac-tor. Overexpression of Skp2 is associated with poor prognosis and metastasis in many cancers and is a well validated drug target. In a recent report, Chart et al. have iden-tified an Skp2 inhibitor that selectively impairs Skp2 E3 ligase activity using an integrated virtual high-throughput drug screening and experimental validation approach. This Skp2 inhibitor restricts cancer stemness and potentiates sensitivity to chemotherapeutic agents in multiple ani-mal tumor models. These findings identify a new novel small molecule that targets the Skp2 and reduces tumor growth by attenu-ating aerobic glycolysis and inducing cel-lular senescence.