背景：乙型肝炎病毒相关肝细胞癌（hepatitis B virus-hepatocellular carcinoma，HBV-HCC）是慢性乙型肝炎（chronic hepatitis B，CHB）的终末期并发症之一，对全球健康和经济构成了重大负担。早期检测对于HBV-HCC的有效管理至关重要，非侵入性筛查生物标志物的发现备受期待。方法：在北京协和医院建立了一个发现队列，包括33 名HBV-HCC 患者、26 名CHB 患者、30 名健康个体和33 名其他癌症患者。使用液相色谱-串联质谱法分析了尿液蛋白质组。通过免疫组织化学验证了HBV-HCC及邻近正常肝组织中的候选生物标志物。利用逻辑回归开发了一个诊断面板。该面板在20名HBV-HCC和40名CHB患者的横断面队列中通过多重靶向蛋白质组学进一步验证。结果：17种尿液蛋白在HBV-HCC患者中特异性上调。其中，异质核糖核蛋白M（heterogeneous ribonucleoprotein M，HNRNPM）、粘附G 蛋白偶联受体G1（adhesion G protein-coupled receptor G1，ADGRG1）、载脂蛋白C1（apolipoproteinC1，APOC1）和RAS 样原癌基因A（RAS-like proto-oncogene A，RALA）在HBVHCC组织中相较于邻近正常肝组织富集。这四种尿液蛋白（4UP）被整合到一个诊断面板中，在发现队列中实现了接收者操作特征曲线下面积（area under the receiveroperating characteristic curve，AUROC）为0.828。在验证队列中，4UP面板展示了0.813的AUROC，证实了其诊断潜力。结论：本研究强调了尿液蛋白质组学在识别生物标志物和解析HBV-HCC发病机制中的潜力，并提出了HNRNPM、ADGRG1、APOC1 和RALA 的4UP 面板，以供进一步研究测试。

Background. HBV-related HCC (HBV-HCC) is one of the terminal complications of chronic hepatitis B (CHB), posing a significant global health and economic burden. Early detection is crucial for effective management of HBV-HCC, and noninvasive screening biomarkers are expected. Methods. A discovery cohort comprising 33 HBV-HCC patients, 26 CHB patients, 30 healthy individuals, and 33 other cancer patients was established at Peking Union Medical College Hospital. Urinary proteomes were analyzed using liquid chromatography-tandem mass spectrometry. Immunohistochemistry was performed to validate candidate biomarkers in HBV-HCC and adjacent normal liver tissues. A diagnostic panel was developed using logistic regression. The panel was further validated in a cross-sectional cohort of 20 HBV-HCC and 40 CHB patients using multiplexed targeted proteomics. Results. 17 urinary proteins were specifically upregulated in HBV-HCC patients. Among these, heterogeneous ribonucleoprotein M (HNRNPM), adhesion G protein-coupled receptor G1 (ADGRG1), apolipoprotein C1 (APOC1), and RAS-like proto-oncogene A (RALA) were enriched in HBV-HCC tissues compared to adjacent normal liver tissues. These four urinary proteins (4UP) were integrated into a diagnostic panel, achieving an area under the receiver operating curve (AUROC) of 0.828 in the discovery cohort. In the validation cohort, the 4UP panel demonstrated an AUROC of 0.813, confirming its diagnostic potential. Conclusions. This study underscores the potential of urinary proteomics in identifying biomarkers and dissecting pathogenesis for HBV-HCC, and presents the 4UP panel of HNRNPM, ADGRG1, APOC1, and RALA to be tested in further investigations.