This perception is consistent with our previous study on genomics and clone evolution of multi-stage ESCC development, showing that NOTCH1 mutant clones are prevalent in normal and precancerous esophageal epithelium but vanish mostly in ESCC.8 More importantly, in the present study, we have further demonstrated that targeting the NOTCH1 signaling pathway, such as the USP5 enzyme, holds significant therapeutic potential for ESCC, in line with the important role of this angiogenesis pathway in ESCC. Here, USP5 is linked to esophageal squamous cell carcinoma.