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

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dc.contributor.authorKang, Zheng
dc.contributor.authorFengjie, Hao
dc.contributor.authorMedrano García, Sandra
dc.contributor.authorChaobo, Chen
dc.contributor.authorMorán Blanco, Laura
dc.contributor.authorPeligros Gómez, María Isabel
dc.contributor.authorVaquero Martín, Francisco Javier
dc.contributor.authorBañares Cañizares, Rafael
dc.contributor.authorGómez Del Moral Martín-Consuegra, Manuel María
dc.contributor.authorRegueiro González-Barros, José Ramón
dc.contributor.authorMartínez Naves, Eduardo
dc.contributor.authorNevzorova, Yulia
dc.contributor.authorFernández Malavé, Edgar Gonzalo
dc.contributor.authorCubero Palero, Francisco Javier
dc.date.accessioned2024-03-08T09:26:32Z
dc.date.available2024-03-08T09:26:32Z
dc.date.issued2023-08-10
dc.description.abstractProgressive 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.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipUnión Europea
dc.description.sponsorshipMinisterio de Ciencia e Innovación y Universidades
dc.description.sponsorshipComunidad de Madrid
dc.description.statuspub
dc.identifier.citationZheng 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
dc.identifier.doi10.1038/s41419-023-06029-y
dc.identifier.issn2041-4889
dc.identifier.officialurlhttps://www.nature.com/articles/s41419-023-06029-y
dc.identifier.pmid37563155
dc.identifier.relatedurlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415403/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/102056
dc.issue.numberArticle number: 514 (2023)
dc.journal.titleCell death diseases
dc.language.isoeng
dc.publisherSpringer Nature
dc.relation.projectIDFEDER
dc.relation.projectIDHORIZON-HLTH-2022-STAYHLTH-02
dc.relation.projectIDRTI2018-095673-B-I00
dc.relation.projectIDPID2020-11782RB-I00
dc.relation.projectIDPID2020-117941RB-I00
dc.relation.projectIDAMMF 2018/117
dc.relation.projectIDS2022/BMD-7409
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu612.017
dc.subject.keywordHomeostasis
dc.subject.keywordPathogenesis
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmInmunología
dc.subject.unesco24 Ciencias de la Vida
dc.subject.unesco2412 Inmunología
dc.titleNeuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number14
dspace.entity.typePublication
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