Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC.

中文翻译：

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senolytic 鸡尾酒达沙替尼 + 槲皮素可轻度加剧肥胖和年龄依赖性肝病进展


非酒精性脂肪性肝病（NAFLD）越来越普遍，并且在预防和治疗方面提出了越来越大的挑战。少数受影响的患者会出现炎症，随后出现纤维化、肝硬化和肝细胞癌 (HCC)。 HCC 是癌症相关死亡的主要原因。在 NAFLD 诱导的 HCC 过程中，衰老细胞数量的增加与年龄相关的组织退化相关。 Senolytics 是选择性靶向衰老细胞的有前途的药物。先前的研究表明，虽然抗衰老药物达沙替尼和槲皮素 (D + Q) 的组合可以减少小鼠的 NAFLD，但 D + Q 在去除人 HCC 异种移植小鼠中阿霉素诱导的 β-gal 阳性衰老细胞方面缺乏功效。 D + Q 是否对 NAFLD-炎症-HCC 的年龄相关谱有影响仍不清楚。在这里，我们利用了一个已建立的与年龄和肥胖相关的 HCC 模型，即低剂量二乙基亚硝胺 (DEN)/高脂肪饮食 (HFD)，这是一种在 9 个月的较长时间内促进肝脏炎症和肿瘤发生的治疗方案。每组小鼠被创建为四组：第一组包括未治疗的对照小鼠；第二组包括未治疗的小鼠。第2组包括用D+Q治疗的小鼠；第 3 组包括接受 DEN/HFD 方案的小鼠；第 4 组包括接受 DEN/HFD 方案并给予 D + Q 的小鼠。在化学/饮食方案结束时，我们通过组织病理学、qPCR 和免疫印迹方法分析了肝损伤和细胞衰老。出乎意料的是，D + Q 加剧了 DEN/HFD 小鼠模型中的肝脏疾病进展，略微增加了组织学损伤和肿瘤发生，但对衰老细胞的清除没有影响。 总之，使用完全重现 NAFLD 的动物模型，我们证明这些化合物对与年龄相关的 NAFLD 诱发的 HCC 无效。