Publicaciones científicas
Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
Kang Zheng # 1 2 3, Fengjie Hao # 1 2 4, Sandra Medrano-Garcia # 1 2, Chaobo Chen # 1 5 6, Feifei Guo 7, Laura Morán-Blanco 1, Sandra Rodríguez-Perales 8, Raúl Torres-Ruiz 8, María Isabel Peligros 9, Javier Vaquero 10 11 12, Rafael Bañares 10 11 12, Manuel Gómez Del Moral 2 13, José R Regueiro 1 2, Eduardo Martínez-Naves 1 2, Mohamed Ramadan Mohamed 14, Rocío Gallego-Durán 11 15, Douglas Maya 11 15, Javier Ampuero 11 15, Manuel Romero-Gómez 11 15, Albert Gilbert-Ramos 11 16, Sergi Guixé-Muntet 11 16, Anabel Fernández-Iglesias 11 16, Jordi Gracia-Sancho 11 16 17, Mar Coll 11 18, Isabel Graupera 11 18 19, Pere Ginès 11 17 19, Andreea Ciudin 20, Jesús Rivera-Esteban 21, Juan M Pericàs 11 21, María Dolores Frutos 22, Bruno Ramos Molina 11 23, José María Herranz 11 24 25, Matías A Ávila 11 24 25, Yulia A Nevzorova 1 11 12, Edgar Fernández-Malavé 1 2, Francisco Javier Cubero 26 27 28
Abstract
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.
CITA DEL ARTÍCULO Cell Death Dis. 2023 Aug 10;14(8):514. doi: 10.1038/s41419-023-06029-y.
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