Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the end-stage of chronic liver diseases, including metabolic-associated steatohepatitis (MASH), an advanced form of metabolic dysfunction-associated steatotic liver disease. The incidence of MASH-driven HCC is expected to continue rising throughout the world due to its association with the obesity and type 2 diabetes epidemic.1 HCC has a poor prognosis with frequent recurrence and intrahepatic metastasis and effective treatment options, such as local ablative therapies, resection or transplantation are mainly limited to early disease stages.1 Unfortunately, the therapeutic armamentarium for HCC is limited, ineffective and subject to secondary or acquired chemoresistance indicating the urgent need to understand the molecular mechanisms leading to MASH-HCC that will allow the identification of new therapeutic targets for the treatment of MASH-HCC development. Although targeting programmed death-ligand 1/programmed cell death protein-1 (PD-1) in the tumour immune microenvironment (TIME) with immune checkpoint inhibitors has shown promising results in different cancer types, the impact of this approach in HCC is somewhat less effective, particularly in MASH-driven HCC tumours which harbour a unique TIME with an accumulation of an exhausted T-cell subsets (CD8+ PD-1+) contributing to the refractory response to anti-PD-1 therapy.2 Since the description that the type rather than the amount of fat drives the transition from steatosis to MASH,3 cholesterol has emerged as a crucial player in MASH pathogenesis and MASH-driven HCC development in part through the generation of bile acids (BAs) via the alternative pathway in which mitochondrial cholesterol is metabolised to the oxysterol 27-hydroxycholesterol to fuel BAs synthesis.4 Previous studies demonstrated that de novo cholesterol synthesis in the mevalonate pathway propels MASH progression5 with a crucial role of squalene epoxidase (SLQE) in MASH-HCC development whose expression is associated with poor outcome in patients with MASH-HCC. …

中文翻译：

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胆固醇的新技巧推动 MASH-HCC：对免疫疗法的影响


肝细胞癌 （HCC） 是最常见的肝癌类型，也是慢性肝病的终末期，包括代谢相关脂肪性肝炎 （MASH），一种代谢功能障碍相关的脂肪性肝病的晚期形式。由于 MASH 驱动的 HCC 与肥胖和 2 型糖尿病流行有关，预计其发病率将在世界范围内继续上升。HCC 预后较差，频繁复发和肝内转移，有效的治疗方案，如局部消融治疗、切除或移植主要限于疾病早期阶段。 HCC 的治疗手段有限、无效且容易受到继发性或获得性化疗耐药的影响，这表明迫切需要了解导致 MASH-HCC 的分子机制，以便确定治疗 MASH-HCC 发展的新治疗靶点。尽管在肿瘤免疫微环境 （TIME） 中用免疫检查点抑制剂靶向程序性死亡配体 1/程序性细胞死亡蛋白-1 （PD-1） 在不同癌症类型中显示出有希望的结果，但这种方法对 HCC 的影响不太有效，特别是在 MASH 驱动的 HCC 肿瘤中，这些肿瘤具有独特的 TIME，积累了耗竭的 T 细胞亚群 （CD8+ PD-1+），导致对抗 PD-1 治疗的难治性反应。2 由于脂肪的类型而不是脂肪量驱动从脂肪变性向 MASH 的转变，3 胆固醇已成为 MASH 发病机制和 MASH 驱动的 HCC 发展的关键参与者，部分原因是通过线粒体胆固醇代谢为氧甾醇 27-羟基胆固醇以推动 BA 合成的替代途径产生胆汁酸 （BA）。角鲨烯环氧化物酶 （SLQE） 在 MASH-HCC 发展中起关键作用，推动 MASH 进展5，其表达与 MASH-HCC 患者的不良预后相关。 …