慢性乙型肝炎 - 肝硬化 - 肝细胞癌（简称「肝癌三部曲」）是中国肝细胞癌（HCC）发生过程中关键的演化阶段。以往关于HCC早期诊断生物标志物的研究仅限于HCC的晚期，而未关注CLH的演化过程。通过生物信息学分析筛选出与CLH高度相关的11个单调变化差异表达基因（MCDEGs），进一步确定需要进行研究的KPNA2。采用酶联免疫吸附实验（ELISA）检测不同CLH状态下的血清KPNA2表达，使用单变量和多变量Cox回归方法构建了一个多项式模型。单细胞RNA-seq和批量RNA-seq研究揭示了KPNA2与HCC免疫浸润和HCC中的细胞周期通路的关系。CLH中KPNA2的血清表达呈单调上调趋势，并有助于诊断不同CLH状态。此外，慢性乙型肝炎（CHB）患者、肝硬化（LC）患者和肝细胞癌（HCC）患者根据血清KPNA2表达被分类为不同亚组。因此，不同血清KPNA2表达的患者表现出不同的临床病理特征。多项式模型在预测发展为CHB患者或LC患者的HCC风险中的AUC值为0.959.最后，我们发现KPNA2表达与HCC对四种化疗药物的IC50值呈负相关。KPNA2是诊断不同CLH状态的新型血清生物标志物，监测CLH的动态演化，并且是干预CLH进展的新疗法目标。© 2023. 作者，独家授权给Springer-Verlag GmbH Germany，Springer Nature的一部分。

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.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.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.