Chronic hepatitis B-liver cirrhosis-hepatocellular carcinoma (CLH), commonly called the "liver cancer trilogy", is a crucial evolutionary phase in the emergence of hepatocellular carcinoma (HCC) in China. Previous studies on early diagnostic biomarkers of HCC were limited to the end-stage of HCC and did not focus on the evolutionary process of CLH., 11 monotonically changing differentially expressed genes (MCDEGs) highly correlated with CLH were screened through bioinformatic analysis and KPNA2 was identified for further research. The serum KPNA2 expression in different CLH states was detected by Enzyme linked immunosorbent assay (ELISA). A nomogram model was constructed using univariate and multivariate Cox regression methods., {AbstractText=The single-cell RNA-seq and bulk RNA-seq revealed that KPNA2 related to immune infiltration in HCC and may participate in cell cycle pathways in HCC. The serum KPNA2 expression was monotonically upregulated in CLH and was valuable for diagnosing different CLH states. Besides, chronic hepatitis B(CHB) patients, liver cirrhosis (LC) patients, and HCC patients were classified into subgroups with distinct serum KPNA2 expressions. Accordingly, patients with different serum KPNA2 expressions displayed various clinicopathological features. The AUC value of the nomogram model was 0.959 in predicting the likelihood of developing HCC in CHB patients or LC patients. Finally, we found that KPNA2 expression was negatively correlated with the IC50 of four chemotherapeutic drugs in HCC.}, KPNA2 was a novel serum biomarker for diagnosing different CLH states, monitoring the dynamic evolution of CLH, and a new therapeutic target for intervening in the progression of CLH.