RT Journal Article
T1 Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
A1 Kang, Zheng
A1 Fengjie, Hao
A1 Medrano García, Sandra
A1 Chaobo, Chen
A1 Morán Blanco, Laura
A1 Peligros Gómez, María Isabel
A1 Vaquero Martín, Francisco Javier
A1 Bañares Cañizares, Rafael
A1 Gómez Del Moral Martín-Consuegra, Manuel María
A1 Regueiro González-Barros, José Ramón
A1 Martínez Naves, Eduardo
A1 Nevzorova, Yulia
A1 Fernández Malavé, Edgar Gonzalo
A1 Cubero Palero, Francisco Javier
AB Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
PB Springer Nature
SN 2041-4889
YR 2023
FD 2023-08-10
LK https://hdl.handle.net/20.500.14352/102056
UL https://hdl.handle.net/20.500.14352/102056
LA eng
NO Zheng K, Hao F, Medrano-Garcia S, Chen C, Guo F, Morán-Blanco L, Rodríguez-Perales S, Torres-Ruiz R, Peligros MI, Vaquero J, Bañares R, Gómez Del Moral M, Regueiro JR, Martínez-Naves E, Mohamed MR, Gallego-Durán R, Maya D, Ampuero J, Romero-Gómez M, Gilbert-Ramos A, Guixé-Muntet S, Fernández-Iglesias A, Gracia-Sancho J, Coll M, Graupera I, Ginès P, Ciudin A, Rivera-Esteban J, Pericàs JM, Frutos MD, Ramos Molina B, Herranz JM, Ávila MA, Nevzorova YA, Fernández-Malavé E, Cubero FJ. Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis. Cell Death Dis. 2023 Aug 10;14(8):514. doi: 10.1038/s41419-023-06029-y
NO Unión Europea
NO Ministerio de Ciencia e Innovación y Universidades
NO Comunidad de Madrid
DS Docta Complutense
RD 22 ago 2024