Details

Autor(en) / Beteiligte

• Zheng, Kang
• Hao, Fengjie
• Medrano-Garcia, Sandra
• Chen, Chaobo
• Guo, Feifei
• Morán-Blanco, Laura
• Rodríguez-Perales, Sandra
• Torres-Ruiz, Raúl
• Peligros, María Isabel
• Vaquero, Javier
• Bañares, Rafael
• Gómez del Moral, Manuel
• Regueiro, José R.
• Martínez-Naves, Eduardo
• Mohamed, Mohamed Ramadan
• Gallego-Durán, Rocío
• Maya, Douglas
• Ampuero, Javier
• Romero-Gómez, Manuel
• Gilbert-Ramos, Albert
• Guixé-Muntet, Sergi
• Fernández-Iglesias, Anabel
• Gracia-Sancho, Jordi
• Coll, Mar
• Graupera, Isabel
• Ginès, Pere
• Ciudin, Andreea
• Rivera-Esteban, Jesús
• Pericàs, Juan M.
• Frutos, María Dolores
• Ramos Molina, Bruno
• Herranz, José María
• Ávila, Matías A.
• Nevzorova, Yulia A.
• Fernández-Malavé, Edgar
• Cubero, Francisco Javier

Titel

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Ist Teil von

• Cell death & disease, 2023-08, Vol.14 (8), p.514-514, Article 514

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 (CCl 4 ) 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 CCl 4 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 CCl 4 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.