随着肥胖流行病的不断扩大，代谢功能障碍相关的脂肪性肝炎（MASH，以前称为 NASH）驱动的肝细胞癌（HCC）的患病率预计将在全球范围内上升，因此对治疗干预措施产生了巨大的需求。我们之前发现了凋亡拮抗转录因子（AATF）的上调，这与促进从 MASH 进展为 HCC 有关。本研究的目的是探讨姜黄素的干预是否可以减轻AATF介导的MASH，抑制肿瘤生长，并阐明其潜在机制。采用模拟人类 MASH-HCC 的临床前小鼠模型，使小鼠接受普通饮食水 (CDNW) 或西方饮食糖水 (WDSW) 以及极低剂量的四氯化碳（CCl4 - 0.2μL/g，每周） 。接受姜黄素 (CUR) 和 WDSW/CCl4 治疗的小鼠表现出显着的改善，包括肝酶降低、血脂异常、脂肪变性、炎症和肝细胞膨胀。姜黄素治疗还抑制肝脏炎症、纤维形成和致癌标志物的表达。值得注意的是，在 WDSW/CCl4 小鼠和人 HCC 细胞中，姜黄素处理后，AATF 的表达显着降低。相比之下，姜黄素上调 MASH 肝脏和 HCC 细胞中的 Kruppel 样因子 4 (KLF4)，而后者会下调 sp1（特异性蛋白 1）的表达。因此，姜黄素治疗通过 KLF4-Sp1 信号通路下调 AATF 的表达，有效抑制 MASH 向 HCC 的进展。这些临床前研究结果在姜黄素和 AATF 之间建立了一种新的分子联系，可减少肝癌的发生，并为开发姜黄素作为人类 MASH-HCC 的可行治疗方法提供了强有力的理论依据。© 2023 Wiley periodicals LLC。

In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)- driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF-mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH-HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4 - 0.2 μL/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4 exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4 mice and human HCC cells. In contrast, curcumin upregulated Kruppel-like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein-1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4-Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH-HCC in humans.© 2023 Wiley Periodicals LLC.