由于术后复发率高和靶向药物的有效性有限，肝细胞癌（HCC）带来了巨大的治疗挑战。研究人员已经确定癌症干细胞（CSC）独特的代谢特征是癌症复发、转移和耐药性的主要驱动因素。因此，为了解决治疗难题，本研究重点关注将 CSC 代谢重编程作为一种新的治疗策略。与亲本细胞相比，HCC CSC 表现出较高的脂肪酸 (FA) 代谢。为了专门针对 CSC 中的 FA 代谢，我们利用了浅蓝素，一种脂肪酸合酶 (FASN) 抑制剂。令人惊讶的是，浅蓝菌素可以减弱 CSC 样特征，包括干性基因表达、球形性、致瘤性和转移潜力。此外，索拉非尼（一种多激酶抑制剂）用作晚期 HCC 的靶向治疗，与浅蓝素联合使用，显示出巨大的协同效应，特别是在 CSC 中。重要的是，我们的 RNA 测序分析表明，淀粉样蛋白前体 (APP) 是 FASN 调节​​ CSC 特性的关键下游效应子。我们发现 APP 在 CSC 的特性中起着至关重要的作用，而这种特性可以被浅蓝素抑制。通过关注 FA 代谢，本研究确定 FASN/APP 轴是开发更有效的晚期 HCC 治疗策略的可行目标。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, in order to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. In order to specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs' characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.