Protein 2‐hydroxyisobutyrylation (Khib) modification of NAT10 is increased in metastatic esophageal cancer, facilitating its interaction with deubiquitylase USP39 and enhancing NAT10 protein stability. NAT10‐mediated ac4C acetylation of NOTCH3 promotes metastasis of esophageal cancer. Here, NAT10 is linked to esophageal cancer.