LOX-1 rewires glutamine ammonia metabolism to drive liver fibrosis

• Published in: Molecular metabolism (Germany) Vol. 96; p. 102132
• Main Authors: Huang, Ruihua, Cui, Hanyu, Yahya Ali Alshami, Mohammed Abdulaziz, Fu, Chuankui, Jiang, Wei, Cai, Mingyuan, Zhou, Shuhan, Zhu, Xiaoyun, Hu, Changping
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.06.2025; Elsevier
• Subjects: Ammonia - metabolism; Animals; GLS; Glutaminase - metabolism; Glutamine - metabolism; Hepatic Stellate Cells - metabolism; Humans; Liver - metabolism; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; LOX-1; Male; Mice; Original; Rats; Rats, Sprague-Dawley; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - metabolism; Urea cycle; Urea cycle; Liver fibrosis; LOX-1; GLS
• DOI: 10.1016/j.molmet.2025.102132
• ISSN: 2212-8778

Liver fibrosis is a crucial condition for evaluating the prognosis of chronic liver disease. Lectin-1ike oxidized low density lipoprotein receptor-1 (LOX-1) has been shown potential research value and therapeutic targeting possibilities in different fibrotic diseases. However, the role of LOX-1 and the underlying mechanisms in liver fibrosis progression remain unclear. LOX-1 expression was detected in liver tissues from patients and rodents with liver fibrosis. LOX-1 knockout rats were subjected to CCl4 or methionine and choline-deficient diet (MCD) to induce liver fibrosis. Transcriptomic and metabolomics analysis were used to investigate the involvement and mechanism of LOX-1 on liver fibrosis. We found that LOX-1 exacerbated liver fibrosis by promoting hepatic stellate cells (HSCs) activation. LOX-1 deletion reversed the development of liver fibrosis. We further verified that LOX-1 drove liver fibrosis by reprogramming glutamine metabolism through mediating isoform switching of glutaminase (GLS). Mechanistically, we revealed the crucial role of the LOX-1/OCT1/GLS1 axis in the pathogenesis of liver fibrosis. Moreover, LOX-1 rewired ammonia metabolism by regulating glutamine metabolism–urea cycle to drive the progression of liver fibrosis. Our findings uncover the pivotal role of LOX-1 in the progression of liver fibrosis, enrich the pathological significance of LOX-1 regulation of hepatic ammonia metabolism, and provide an insight into promising targets for the therapeutic strategy of liver fibrosis, demonstrating the potential clinical value of targeting LOX-1 in antifibrotic therapy. [Display omitted] •LOX-1 expression was significantly increased in the livers of liver fibrosis patients and animal models.•LOX-1 drove the progression of liver fibrosis by promoting the activation of hepatic stellate cells.•LOX-1 reprogrammed glutamine metabolism by mediating GLS isotype swift.•LOX-1 up-regulated GLS1 expression via enhancement of transcriptional regulation of OCT1.•LOX-1 rewired glutamine metabolism and urea cycle to disrupt ammonia homeostasis driving liver fibrosis.