胆固醇代谢的重新布线在肝癌发生过程中塑造了免疫重塑
Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.
摘要(中文译文)
胆固醇代谢、肝细胞癌（HCC）与肿瘤免疫微环境日益被认为是代谢功能障碍相关脂肪性肝病/代谢功能障碍相关脂肪性肝炎相关肝细胞癌（MASLD/MASH-HCC）的相互关联驱动因素。然而，肝癌发生过程中的胆固醇失调常被作为孤立通路或单一阶段事件加以讨论，且在人HCC组织、临床前HCC模型及非HCC系统中的证据强度存在差异。本综述整合机制性、空间多组学及转化性证据，强调胆固醇稳态失衡是合成、摄取、酯化、外排和转化的阶段特异性和细胞类型特异性重编程，而非均一的代谢增高。在慢性代谢性肝病中，固醇调节元件结合蛋白2（SREBP2）-SREBP裂解激活蛋白（SCAP）激活、胆汁酸-法尼醇X受体（FXR）反馈受损、游离胆固醇负荷及氧固醇蓄积可能将肝细胞应激与星状细胞活化、巨噬细胞重塑、炎症及纤维化联系起来。在癌前转变和早期HCC阶段，角鲨烯环氧酶（SQLE）、固醇O-酰基转移酶1（SOAT1）、法尼基二磷酸法尼基转移酶1（FDFT1）、24-脱氢胆固醇还原酶（DHCR24）及SCAP调控回路可能支持膜重塑、致癌信号传导、代谢自主性及免疫监视受损，尽管其证据水平参差不齐。在晚期和转移性HCC中，空间分辨研究提示胆固醇活跃的肿瘤区域可能与耗竭T细胞、肿瘤相关巨噬细胞（TAM）、髓源性抑制细胞（MDSC）、细胞外囊泡信号传导及氧固醇介导的通讯相耦合。我们进一步讨论与阶段匹配的诊断和治疗机会，提出胆固醇代谢重编程作为HCC发生、进展、复发及治疗耐药的一个产生假设且部分验证的框架。
Abstract
Cholesterol metabolism, hepatocellular carcinoma (HCC), and the tumor immune microenvironment are increasingly recognized as interconnected drivers of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis-related HCC (MASLD/MASH-HCC). However, cholesterol dysregulation during hepatocarcinogenesis is often discussed as isolated pathways or single-stage events, and evidence strength differs across human HCC tissues, preclinical HCC models, and non-HCC systems. This review integrates mechanistic, spatial multi-omics, and translational evidence to highlight cholesterol dyshomeostasis as a stage- and cell-type-specific rewiring of synthesis, uptake, esterification, efflux, and conversion rather than a uniform metabolic increase. In chronic metabolic liver disease, sterol regulatory element-binding protein 2 (SREBP2)-SREBP cleavage-activating protein (SCAP) activation, impaired bile acid-farnesoid X receptor (FXR) feedback, free-cholesterol loading, and oxysterol accumulation may connect hepatocyte stress with stellate-cell activation, macrophage remodeling, inflammation, and fibrosis. During preneoplastic transition and early HCC, squalene epoxidase (SQLE), sterol O-acyltransferase 1 (SOAT1), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), 24-dehydrocholesterol reductase (DHCR24), and SCAP-regulatory circuits may support membrane remodeling, oncogenic signaling, metabolic autonomy, and impaired immune surveillance, although their evidence levels vary. In advanced and metastatic HCC, spatially resolved studies suggest cholesterol-active tumor regions may be coupled to exhausted T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), extracellular vesicle signaling, and oxysterol-mediated communication. We further discuss stage-aligned diagnostic and therapeutic opportunities, proposing cholesterol metabolic rewiring as a hypothesis-generating and partially validated framework for HCC initiation, progression, recurrence, and therapeutic resistance.
如何引用
AMA
Wentao Ma, Fengxu Yan, Yu Cheng, Guoqing Zhang, Yanxi Mu, Zhiqiang Zhang, et al. Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1884948.
APA
Wentao Ma, Fengxu Yan, Yu Cheng, Guoqing Zhang, Yanxi Mu, Zhiqiang Zhang, et al (2026). Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1884948
GB/T 7714
Wentao Ma, Fengxu Yan, Yu Cheng, Guoqing Zhang, Yanxi Mu, Zhiqiang Zhang, et al. Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1884948.
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