In summary, through multiomics analysis of DNA methylation, transcriptome, and single-cell atlas data, this study identified novel NEC-related genes potentially regulated by DNA methylation, namely, ADAP1, GUCA2A, IL22RA1 and MISP, and their aberrant promoter CpG methylation status in NEC was further verified. Here, IL22RA1 is linked to necrotizing enterocolitis.