不醇性脂肪肝（NASH）相关肝细胞癌（HCC）的全身治疗效果尚不明确。本研究评估了索拉非尼在NASH相关HCC模型中，基于与主要肝癌发生通路和血管生成相关的分子标志物表达的影响。用高脂和胆碱不足饮食和二乙基亚硝胺（100 mg/L）的饮用水联合诱导40只雄性大鼠NASH-HCC，持续13和16周。诱导期结束后，大鼠每日腔内投药盐水（对照组）或索拉非尼（5 mg/kg/天）持续3周。此后，对动物进行安乐死，并采集肝结节样本进行组织病理学分析和HEP-PAR-1、谷氨酸合成酶、VEGF、survivin、β-连环蛋白和p53的免疫组织化学评估。使用半定量评分法对VEGF、survivin和β-连环蛋白进行分析，对p53则确定阳性细胞的百分比。结果通过Wilcoxon检验或学生t检验进行处理。两种方案都有效诱导了HCC，其中大部分HCC为中低分化。与对照组相比，索拉非尼治疗动物13周生成的HCC显示出VEGF和p53的表达降低（p = 0.03；p = 0.04）。β-连环蛋白和survivin差异不显著。两个对照组（13周 vs. 16周）之间的VEGF和p53表达存在显著降低（p < 0.01）。p53和VEGF是评估索拉非尼疗效的有希望的生物标志物，而survivin和β-连环蛋白则无用。16周对照组的p53和VEGF的免疫组织化学表达降低可能表明HCC的代谢状态不同。© 2023. 作者，授权给斯普林格自然出版集团有限公司。

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100 mg/L) administration in the drinking water for 13 and 16 weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5 mg/kg/day) for 3 weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13 weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16 weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16 week control group may indicate a different metabolic status of HCC.© 2023. The Author(s), under exclusive licence to Springer Nature B.V.