Wang Hao, Xu Xiaoqian, Shi Lichen, Huang Cheng, Sun Yameng, You Hong, Jia Jidong, He You-Wen, Kong Yuanyuan
National Clinical Research Center for Digestive Disease, State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Clinical Epidemiology and Evidence-Based Medicine, Beijing Clinical Research Institute, Beijing, China.
Hepatol Int. 2025 Jan 21. doi: 10.1007/s12072-024-10775-2.
Our previous research demonstrated that growth differentiation factor 15 (GDF15) exhibited superior predictive capability for metabolic dysfunction-associated steatohepatitis (MASH) development with an AUC of 0.86 at 10 years before disease diagnosis. However, the specific pathways and molecular mechanisms associated with GDF15 expression during MASH development remain to be fully investigated in humans.
A nested case-control study comprising a MASH group of 78 individuals and three age- and sex-matched control groups (156 metabolic dysfunction-associated steatosis, 78 viral hepatitis, and 156 normal liver controls) was conducted. The baseline levels of GDF15-related transcription factors and upstream signaling pathways associated with the identified transcription factors were analysed prospectively.
The significantly higher level of nuclear factor of activated T cells 3 (NFATC3), a transcription factor for GDF15, was identified in the circulation in MASH patients compared to controls. Expression of the non-canonical Wnt signaling pathway that is upstream of NFATC3, and its related proteins CTHRC1, FRZB, SFRP1, and SFRP4, were highest in the MASH group, suggesting a non-canonical Wnt signaling/NFATC3/GDF-15 cascade in MASH disease pathogenesis. A predictive model for MASH development based on four biomarkers (CTHRC1, FRZB, NFATC3, and GDF15) showed an AUC of 0.90 at 10 years. A protein-clinical model that included these four circulating proteins and BMI yielded an AUC of 0.93 at 10 years.
Non-canonical Wnt signaling pathway may activate NFATC3 to promote GDF15 expression in MASH disease pathogenesis. These molecular mechanisms provide novel insights for developing targeted therapies that could modulate the non-canonical Wnt/NFATC3/GDF15 cascade to prevent/treat MASH.
我们之前的研究表明，生长分化因子15（GDF15）对代谢功能障碍相关脂肪性肝炎（MASH）的发生具有卓越的预测能力，在疾病诊断前10年的曲线下面积（AUC）为0.86。然而，在人类MASH发生过程中，与GDF15表达相关的具体途径和分子机制仍有待充分研究。
进行了一项巢式病例对照研究，包括一个由78名个体组成的MASH组和三个年龄及性别匹配的对照组（156例代谢功能障碍相关脂肪变性、78例病毒性肝炎和156例正常肝脏对照）。前瞻性分析了与GDF15相关的转录因子及其上游信号通路的基线水平。
与对照组相比，在MASH患者的循环中发现，GDF15的转录因子活化T细胞核因子3（NFATC3）水平显著更高。在NFATC3上游的非经典Wnt信号通路及其相关蛋白CTHRC1、FRZB、SFRP1和SFRP4的表达在MASH组中最高，提示在MASH疾病发病机制中存在非经典Wnt信号/NFATC3/GDF-15级联反应。基于四种生物标志物（CTHRC1、FRZB、NFATC3和GDF15）建立的MASH发生预测模型在10年时的AUC为0.90。包含这四种循环蛋白和体重指数（BMI）的蛋白质-临床模型在10年时的AUC为0.93。
非经典Wnt信号通路可能激活NFATC3，从而在MASH疾病发病机制中促进GDF15表达。这些分子机制为开发靶向治疗提供了新的见解，该靶向治疗可调节非经典Wnt/NFATC3/GDF15级联反应以预防/治疗MASH。
