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通过FOXM1/CEBPB轴驱动的细胞状态可塑性的向破坏了肝细胞癌的发育异质性和治疗耐药性

Xiao-Feng Zhang¹, Xiao-Yu Zuo², Yun Zhu²

¹Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China.

Journal of hepatology

|October 3, 2025

概括

肝细胞癌 (HCC) 细胞可塑性驱动瘤异质性和耐药性. 通过RNA干扰疗法向FOXM1/CEBPB轴恢复均性,并在临床前模型中提高治疗疗效.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学遗传学是一个

背景情况:

肝细胞癌 (HCC) 的表型可塑性产生细胞多样性,有助于治疗耐药性.
治理HCC这种发育异质性的基本机制仍然不太清楚.
目前缺乏针对这种可塑性的有效治疗策略.

研究的目的:

确定控制HCC细胞状态转换的关键转录调节剂.
阐明发育异质性在驱动治疗耐药性和免疫逃避中的作用.
评估针对特定监管轴的新型治疗干预措施.

主要方法:

从HCC患者的大量和单细胞RNA测序数据和肝细胞分化模型的分析.
自主调节网络分析以确定转录调节器.
在体外和体内实验,以调查分子机制和治疗潜力.

主要成果:

HCC的进展表现出动态的细胞状态过渡和混乱的发育轨迹.
增加的发育多样性与耐药性基因激活和免疫逃避相关,影响预后.
确定FOXM1/CEBPB轴是发育异质性的主调节器,作为切换开关.
抑制FOXM1促进了瘤发育的一致性,并通过IFN-γ信号传递重新使瘤对免疫监测敏感.
一种针对肝脏FOXM1的新型RNA干扰治疗方法在临床前模型中显示出强大的疗效和耐受性.

结论:

FOXM1/CEBPB轴驱动HCC细胞状态可塑性,导致发育异质性和治疗耐药性.
用RNA干扰疗法准肝脏FOXM1显示出在HCC治疗中临床应用的重大前景.

关键词:

细胞状态开关细胞状态开关药物耐药性药物耐药性药物耐药性在RNAi疗法中使用RNAi疗法.瘤异质性瘤异质性瘤的可塑性瘤的可塑性

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