UHRF1 is a pivotal regulator of DNA methylation, and it engages in complex interactions with epigenetic modulators such as DNMT1, DNMT3A/B, HDAC1, and PRMT5 to facilitate DNA methylation maintenance and histone modifications that govern gene expression.[18, 29, 30] Therefore, we hypothesized that UHRF1 might bind to UMRs, thereby increasing DNA methylation levels and consequently activating NKX2‐5 and LHX1 transcription in ESCC cells. This evidence concerns the gene NKX2-5 and esophageal squamous cell carcinoma.