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

哺乳动物肝脏的组织微环境中包含异质细胞类型，这些细胞类型在疾病状态下经历病理生理重编程，例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。在这里，我们发现饮食诱导的 NASH 的特点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 细胞的耗尽。脂肪细胞衍生的内分泌因子神经调节蛋白 4 (NRG4) 作为激素检查点，可抑制 NASH 期间的这种病理性重编程。NRG4 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 过表达则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 和延长治疗小鼠的生存方面表现出显着的功效。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。