In:
Cell Death & Disease, Springer Science and Business Media LLC, Vol. 14, No. 8 ( 2023-08-10)
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 (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.
Type of Medium:
Online Resource
ISSN:
2041-4889
DOI:
10.1038/s41419-023-06029-y
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2023
detail.hit.zdb_id:
2541626-1
Bookmarklink