A three-factor logistic model integrating circ-CDYL and its target genes HDGF and HIF1AN discriminates early HCC from adjacent non-tumor tissue with an AUC of 0.73 (95% CI 0.65–0.80), a sensitivity of 75.4% and a specificity of 66.7%, significantly outperforming the conventional biomarker AFP (AUC 0.59). Here, AFP is linked to hepatocellular carcinoma.