Using this data, a model with six cfRNAs (C1QTNF4, SETBP1, CYBA, PCDHB3, HMGA1, and ZNF541) was developed to diagnose HCC, showing high diagnostic efficiency (area under curve (AUC) = 0.905) in the independent validation cohort (HCC, n = 7; CHB, n = 4; healthy individuals, n = 8), suggesting the huge potential of the MOF method for biomarker identification and biological function research of circulating cfRNA/cfDNA. This evidence concerns the gene ZNF541 and hepatocellular carcinoma.