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Título: | Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis |
Autor: | Zheng, Kang; Hao, Fengjie; Medrano-García, 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; Ramadan Mohamed, Mohamed; Gallego-Durán, Rocío CSIC ORCID; Maya-Miles, Douglas CSIC ORCID; Ampuero, Javier CSIC ORCID; Romero-Gómez, Manuel CSIC ORCID CVN; 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. CSIC ORCID; Nevzorova, Yulia A.; Fernández-Malavé, Edgar CSIC; Cubero, Francisco Javier | Palabras clave: | Homeostasis Pathogenesis |
Fecha de publicación: | 10-ago-2023 | Editor: | Nature Publishing Group | Citación: | Cell Death & Disease 14: 514 (2023) | Resumen: | 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. | Descripción: | © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | Versión del editor: | https://doi.org/10.1038/s41419-023-06029-y | URI: | http://hdl.handle.net/10261/352030 | DOI: | 10.1038/s41419-023-06029-y | E-ISSN: | 2041-4889 |
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