2026-04-13T06:21:56Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/101812025-10-24T08:52:22Zcom_2072_378070com_2072_378040com_2072_378071col_2072_378092col_2072_378097

00925njm 22002777a 4500 dc Zheng, Kang author Hao, Fengjie author Medrano-Garcia, Sandra author chaobo, chen author Guo, Feifei author Morán-Blanco, Laura author Ciudin Mihai, Andreea author Rivera-Esteban, Jesús author Pericas, Juan M author 2023-08-30T10:30:34Z 2023-08-30T10:30:34Z 2023-08-10 Homeostasis; Pathogenesis Homeostasis; Patogénesis Homeòstasi; Patogènesi 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. This work was supported by the MICINN Retos RTI2018-095673-B-I00, PID2020-11782RB-I00, PID2020-117941RB-I00, all of which were co-funded with FEDER funds, AMMF 2018/117, COST Action CA17112 and Comunidad de Madrid S2022/BMD-7409. This project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No. 101095679. The research group belongs to the validated Research Groups Ref. 970935 Liver Pathophysiology, 920631 Lymphocyte Immunobiology and IBL-6 (imas12-associated). KZ was supported by the China Scholarship Council. SM-G was supported by a predoctoral scholarship from Complutense University. http://hdl.handle.net/11351/10181 Neuroblastoma Fetge - Malalties - Tractament Oncogens DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Neuroectodermal Tumors, Primitive::Neuroectodermal Tumors, Primitive, Peripheral::Neuroblastoma PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes DISEASES::Digestive System Diseases::Liver Diseases Other subheadings::Other subheadings::Other subheadings::/drug therapy ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::tumores neuroectodérmicos primitivos::tumores neuroectodérmicos primitivos periféricos::neuroblastoma FENÓMENOS Y PROCESOS::fenómenos genéticos::estructuras genéticas::genoma::componentes genómicos::genes::genes de neoplasias::oncogenes ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis