The mechanisms that cause the world’s most common chronic liver disease — Metabolic dysfunction-associated steatotic liver disease (MASLD) — to develop and progress are not still fully understood. Now, a study by the University of Barcelona has identified a new factor involved in the development of the disease: the protein ENT1, which allows the transport of small molecules essential for the functioning of liver cells into the cell. The results of the study, carried out with patients and animal models, open the door to exploring future therapies.
The research, published in the journal Metabolism, is led by Professor Sandra Pérez-Torras, member of the Department of Biochemistry and Molecular Biomedicine at the UB’s Faculty of Biology, the Institute of Biomedicine of the University of Barcelona (IBUB) and the Sant Joan de Déu Research Institute (IRSJD). The study also involved significant contributions from Professor Marçal Pastor-Anglada (UB, IBUB and IRSJD); postdoctoral researcher Aida Mata-Ventosa (UB, IBUB and IRSJD), one of the paper’s co-first authors; and researcher Maria Isabel Hernández-Alvarez (UB and IBUB).
Sonia Fernández-Veledo, from the Southern Catalonia Biomedical Research Institute (IRB CatSud), the Universitat Rovira i Virgili and the CIBER Area for Diabetes and Associated Metabolic Diseases (CIBERDEM), also co-leads the study carried out together with experts from other national and international institutions.
Protection against fat, inflammation and fibrosis
This chronic disease, which is not caused by alcohol consumption but by metabolic disturbances such as obesity, is characterized by the excessive accumulation of fat in the liver and can progress to more severe forms, such as advanced fibrosis or liver cancer.
To uncover the liver mechanisms that contribute to the early stages of the disease, the researchers focused on ENT1, a transporter protein that regulates the entry of small molecules called nucleosides across the plasma membrane. Thus, the team studied the expression of ENT1 — that is, the extent to which the gene responsible for producing this transporter is active — and its impact on liver and whole-body metabolism.
Experiments in mice with and without ENT1 have established a link between this transporter, nucleoside levels — particularly adenosine, a nucleoside involved in regulating inflammation and in cells’ response to stress — and the development of the characteristic alterations associated with the disease.
The results show that ENT1 deficiency reduces adenosine levels in the liver and protects animals against inflammation, fibrosis and excessive fat accumulation in this organ. Moreover, mice lacking ENT1 show improved glucose tolerance and increased insulin sensitivity, suggesting that the transporter’s effects may extend beyond the liver and affect the organism’s overall metabolism.
A different role according to the stage of the disease
Analysis of liver biopsies from patients and gene expression databases has complemented the results of animal models, showing that hepatic ENT1 expression varies throughout the course of MASLD. In the early stages, expression levels are higher in humans and mice, but decrease as the disease progresses. This suggests that this transporter is regulated differently depending on the stage of the pathology.
“The increased expression of ENT1 in the early stages could contribute to transport and uptake of adenosine in the liver, which would be consistent with the onset and early progression of the disease,” the authors explain.
Patient data also reinforce the possible involvement of ENT1 in whole-body metabolism. In individuals with early-stage MASLD, higher ENT1 expression in the liver is associated with elevated insulin levels and a higher HOMA-IR index, an indicator of insulin resistance.
“Overall, these findings identify ENT1 as a regulator of systemic nucleoside metabolism and metabolic homeostasis, and highlight nucleoside transport as a hitherto underappreciated axis contributing to the development and progression of MASLD,” the researchers emphasize.
A therapeutic approach with great potential The results of this study identify this transporter as a potential target for exploring new therapeutic strategies. Moreover, ENT1 is of particular interest because drugs capable of inhibiting its activity already exist, and some of these compounds are already in various phases of clinical development. “Therefore, ENT1 is not an unknown pharmacological target, although its potential use in MASLD still requires much more research, particularly in humans and with larger cohorts,” the researchers conclude.
References
Mata-Ventosa, Aida et al. «Equilibrative nucleoside transporter 1 deficiency protects against diet-induced MASLD and is stage-associated in human liver disease». Metabolism: Clinical and Experimental, 2026. DOI: 10.1016/j.metabol.2026.156710.
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