Zhang Mi, Yuan Weigang, Li Chun, Chen Chanyuan, Liu Xiang, Ma Zhilu, Xiang Yifei, Chen Guisha, Wang Chunxu, Li Lei, Wang Lingli, Xu Zhong, Xu Chuanrui
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
School of Pharmacy, Lanzhou University, Lanzhou, China.
Front Pharmacol. 2025 Apr 28;16:1574039. doi: 10.3389/fphar.2025.1574039. eCollection 2025.
Accumulating evidence indicates that antioxidants promote tumor growth and metastasis after tumor onset in several cancer types. However, whether antioxidants prevent or accelerate hepatic tumorigenesis during steatosis remains unknown. Therefore, we investigated the effects of resveratrol (RES) and N-acetylcysteine (NAC) on hepatocellular carcinoma (HCC) development using two fatty liver mouse models.
High-fat diet (HFD) plus diethylnitrosamine (DEN)- and AKT/Ras-induced primary HCC mouse models were used. The weight, liver weight ratio and the number of HCC tumors were calculated and histological features of mouse HCC tissues were analyzed using immumohistochemical staining such as hematoxylin and eosin staining. Proteomic analysis was used to screen for differences in liver cancer progression between antioxidant-treated HCC and models. Protein inhibitor recovery experiments in mice and cells validate the targets screened by proteomic analysis. The expression of GST-pi, p-JNK and p-p38 signaling molecules in HCC were investigated using Western blotting.
RES and NAC enhance HCC formation in both DEN/HFD and AKT/Ras mice. RES and NAC alleviate hepatosteatosis, and reduce ROS and DNA damage in mice. Proteomic analysis and protein inhibitor recovery assay demonstrated that GST-pi is a therapeutic target for antioxidant-induced hepatocellular carcinoma growth. Mechanistically, RES and NAC decreased p-JNK and p-p38, the two major mitogen-activated protein kinases, in HCC cells. Blockade of GST-pi abrogated the reduction in p-JNK and p-p38 levels and increased apoptosis of HCC cells.
Antioxidants may increase the incidence of HCC in a population with fatty liver, despite reduction in ROS production, by inhibiting GST-pi-MAPK axis.
越来越多的证据表明，抗氧化剂在几种癌症类型的肿瘤发生后会促进肿瘤生长和转移。然而，抗氧化剂在脂肪变性过程中是预防还是加速肝癌发生仍不清楚。因此，我们使用两种脂肪肝小鼠模型研究了白藜芦醇（RES）和N-乙酰半胱氨酸（NAC）对肝细胞癌（HCC）发展的影响。
使用高脂饮食（HFD）联合二乙基亚硝胺（DEN）诱导的原发性肝癌小鼠模型和AKT/Ras诱导的原发性肝癌小鼠模型。计算体重、肝脏重量比和HCC肿瘤数量，并使用苏木精和伊红染色等免疫组织化学染色分析小鼠HCC组织的组织学特征。蛋白质组学分析用于筛选抗氧化剂处理的HCC与模型之间肝癌进展的差异。在小鼠和细胞中进行蛋白质抑制剂恢复实验，以验证蛋白质组学分析筛选出的靶点。使用蛋白质印迹法研究HCC中GST-pi、p-JNK和p-p38信号分子的表达。
RES和NAC在DEN/HFD和AKT/Ras小鼠中均增强了HCC的形成。RES和NAC减轻了肝脂肪变性，并减少了小鼠体内的活性氧（ROS）和DNA损伤。蛋白质组学分析和蛋白质抑制剂恢复试验表明，GST-pi是抗氧化剂诱导的肝细胞癌生长的治疗靶点。从机制上讲，RES和NAC降低了HCC细胞中两种主要的丝裂原活化蛋白激酶p-JNK和p-p38的水平。阻断GST-pi可消除p-JNK和p-p38水平的降低，并增加HCC细胞的凋亡。
抗氧化剂可能通过抑制GST-pi-MAPK轴，增加脂肪肝人群中HCC的发病率，尽管其可减少ROS的产生。
