美国密歇根大学医学中心Jiandie D. Lin团队近日取得重要工作进展，他们研究发现Neuregulin 4可以通过限制肿瘤易感的肝脏微环境来抑制NASH-HCC的生成。相关成果2022年8月15日在线发表于《细胞—代谢》杂志上。

研究人员表明饮食诱导的NASH的特征是诱导肿瘤相关巨噬细胞（TAM）样巨噬细胞和肝脏中细胞毒性CD8⁺ T细胞的耗竭。脂肪细胞来源的内分泌因子Neuregulin 4（NRG4）作为激素检查点，可在NASH期间抑制这种病理性重编程。NRG4的缺乏加剧了易患肿瘤的肝脏免疫微环境和NASH相关HCC的诱导，而转基因NRG4过表达在小鼠中引发了保护作用。在治疗环境中，重组NRG4-Fc融合蛋白在抑制HCC和延长治疗小鼠的存活率方面表现出显著的效力。这些发现为靶向NRG4激素检查点的肝癌治疗干预铺平了道路。

据介绍，哺乳动物肝脏在其组织微环境中包含异质细胞类型，在疾病状态下经历病理生理重编程，如非酒精性脂肪性肝炎（NASH）。NASH患者发生肝细胞癌（HCC）的风险增加。然而，将NASH与肝癌发生联系起来的肝脏微环境重塑的分子和细胞性质仍然不清楚。

附：英文原文

Title: Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment

Author: Peng Zhang, Zhimin Chen, Henry Kuang, Tongyu Liu, Jiaqiang Zhu, Linkang Zhou, Qiuyu Wang, Xuelian Xiong, Ziyi Meng, Xiaoxue Qiu, Ramiah Jacks, Lu Liu, Siming Li, Carey N. Lumeng, Qing Li, Xiang Zhou, Jiandie D. Lin

Issue&Volume: 2022-08-15

Abstract: The mammalian liver comprises heterogeneous cell types within its tissue microenvironmentthat undergo pathophysiological reprogramming in disease states, such as non-alcoholicsteatohepatitis (NASH). Patients with NASH are at an increased risk for the developmentof hepatocellular carcinoma (HCC). However, the molecular and cellular nature of livermicroenvironment remodeling that links NASH to liver carcinogenesis remains obscure.Here, we show that diet-induced NASH is characterized by the induction of tumor-associatedmacrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in theliver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonalcheckpoint that restrains this pathological reprogramming during NASH. NRG4 deficiencyexacerbated the induction of tumor-prone liver immune microenvironment and NASH-relatedHCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. Ina therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potencyin suppressing HCC and prolonged survival in the treated mice. These findings pavethe way for therapeutic intervention of liver cancer by targeting the NRG4 hormonalcheckpoint.

DOI: 10.1016/j.cmet.2022.07.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00309-6