Feng Gong, Targher Giovanni, Byrne Christopher D, He Na, Mi Man, Liu Yi, Zhu Hongbin, Zheng Ming-Hua, Ye Feng
Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Department of Medicine, University of Verona, Verona, Italy.
J Clin Transl Hepatol. 2025 Sep 28;13(9):723-733. doi: 10.14218/JCTH.2025.00270. Epub 2025 Jul 16.
The causal biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) and their clinical value remain unclear. In this study, we aimed to identify biomarkers for MASLD and evaluate their diagnostic and prognostic significance.
We conducted a Mendelian randomization analysis to assess the causal effects of 2,925 molecular biomarkers (from proteomics data) and 35 clinical biomarkers on MASLD. Mediation analysis was performed to determine whether clinical biomarkers mediated the effects of molecular biomarkers. The association between key clinical biomarkers and MASLD was externally validated in a hospital-based cohort (n = 415). A machine learning-based diagnostic model for MASLD was developed and validated using the identified molecular biomarkers. Prognostic significance was evaluated for both molecular and clinical biomarkers.
Six molecular biomarkers-including canopy FGF signaling regulator 4 (CNPY4), ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6), and major histocompatibility complex, class I, A (HLA-A)-and eight clinical biomarkers (e.g., serum total protein (STP)) were identified as causally related to MASLD. STP partially mediated the effect of HLA-A on MASLD (23.61%) and was associated with MASLD in the external cohort (odds ratio = 1.080, 95% confidence interval: 1.011-1.155). A random forest model demonstrated high diagnostic performance (AUC = 0.941 in training; 0.875 in validation). High expression levels of CNPY4 and ENTPD6 were associated with the development of and poorer survival from hepatocellular carcinoma. Low STP (<60 g/L) predicted all-cause mortality (HR = 2.50, 95% confidence interval: 1.22-5.09).
This study identifies six causal molecular biomarkers (e.g., CNPY4, ENTPD6, HLA-A) and eight clinical biomarkers for MASLD. Notably, STP mediates the effect of HLA-A on MASLD and is associated with all-cause mortality.
代谢功能障碍相关脂肪性肝病（MASLD）的因果生物标志物及其临床价值尚不清楚。在本研究中，我们旨在识别MASLD的生物标志物，并评估其诊断和预后意义。
我们进行了孟德尔随机化分析，以评估2925种分子生物标志物（来自蛋白质组学数据）和35种临床生物标志物对MASLD的因果效应。进行中介分析以确定临床生物标志物是否介导分子生物标志物的效应。在一个基于医院的队列（n = 415）中对关键临床生物标志物与MASLD之间的关联进行了外部验证。使用鉴定出的分子生物标志物开发并验证了基于机器学习的MASLD诊断模型。对分子和临床生物标志物的预后意义进行了评估。
六种分子生物标志物——包括冠层FGF信号调节因子4（CNPY4）、外核苷三磷酸二磷酸水解酶6（ENTPD6）和主要组织相容性复合体I类A（HLA-A）——以及八种临床生物标志物（如血清总蛋白（STP））被确定与MASLD存在因果关系。STP部分介导了HLA-A对MASLD的影响（23.61%），并且在外部队列中与MASLD相关（优势比 = 1.080，95%置信区间：1.011 - 1.155）。随机森林模型显示出较高的诊断性能（训练时AUC = 0.941；验证时AUC = 0.875）。CNPY4和ENTPD6的高表达水平与肝细胞癌的发生及较差的生存率相关。低STP（<60 g/L）预测全因死亡率（HR = 2.50，95%置信区间：1.22 - 5.09）。
本研究识别出六种MASLD的因果分子生物标志物（如CNPY4、ENTPD6、HLA-A）和八种临床生物标志物。值得注意的是，STP介导了HLA-A对MASLD的影响，并与全因死亡率相关。
