Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment.
Cell Metab
; 34(9): 1359-1376.e7, 2022 09 06.
Article
en En
| MEDLINE
| ID: mdl-35973424
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma Hepatocelular
/
Neurregulinas
/
Enfermedad del Hígado Graso no Alcohólico
/
Neoplasias Hepáticas
Límite:
Animals
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos