代谢功能障碍相关的脂肪性肝炎驱动的肝细胞癌(MASH-HCC)是一个全球性的临床挑战,对疾病的发病机制了解有限,随后缺乏治疗干预措施。我们先前确定了肿瘤坏死因子-α(TNF-α)在MASH中上调凋亡拮抗转录因子(AATF)。这里,我们研究了TNF-α转化酶(TACE)抑制作为一种有希望的靶向治疗AATF介导的脂肪性肝炎对肝癌发生的影响。在研究中使用了概括人MASH-HCC的临床前鼠模型。C57Bl/6小鼠用食物饮食正常水(CD)或西方饮食糖水(WD)以及低剂量的四氯化碳(CCl4;每周0.2μL·g-1)喂养24周。TACE活动,TNF-α水平,测量AATF表达。用TACE抑制剂Marimastat治疗小鼠12周,其次是肝损伤的分析,纤维化,炎症,和致癌信号。还进行了使用AATF对照和AATF敲低的稳定克隆的体外实验。我们发现在WD/CCl4小鼠中AATF表达上调,在12周时发展为严重的MASH,在24周时发展为HCC晚期纤维化。WD/CCl4小鼠显示TACE活性增加,沉默调节蛋白1(Sirt1)和金属蛋白酶3组织抑制剂(Timp3)的肝表达减少。通过TNF-α的释放证实了SIRT1/TIMP3/TACE轴的参与,上调了AATF,MASH-HCC的关键分子驱动因素。有趣的是,Marimastat抑制TACE减少肝损伤,血脂异常,AATF表达式,和致癌信号,有效预防肝癌发生。此外,Marimastat抑制JNK的激活,ERK1/2和AKT,它们是WD/CCl4小鼠和AATF对照细胞中肿瘤发生的关键调节因子,但对AATF敲低细胞没有影响。这项研究表明,TACE抑制可以防止AATF介导的炎症,纤维化,和MASH-HCC的肿瘤发生,提供治疗干预的潜在目标。
Metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor-alpha (TNF-α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF-α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF-mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH-HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 μL·g-1, weekly) for 24 weeks. TACE activity, TNF-α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF-α, which upregulated AATF, a key molecular driver of MASH-HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF-mediated inflammation, fibrosis, and oncogenesis in MASH-HCC, offering a potential target for therapeutic intervention.