A study identifies the key role of a protein and paves the way for new therapeutic strategies.

The mechanisms that trigger and drive the progression of the most common chronic liver disease worldwide are still not fully understood: metabolic dysfunction-associated steatotic liver disease (MASLD). A new study by the Universitat de Barcelona has now identified a new factor in the development of the disease: the ENT1 protein, which allows small molecules essential for liver cell function to enter cells. The findings, obtained through research involving patients and animal models, pave the way for exploring future therapies.

The research, published in the journal Metabolism, is led by Professor Sandra Pérez-Torras from the Departament de Bioquímica i Biomedicina Molecular of the Facultat de Biologia, the Institut de Biomedicina (IBUB) and the Institut de Recerca Sant Joan de Déu (IRSJD). The study also highlights the contributions of Professor Marçal Pastor-Anglada, Aida Mata-Ventosa, one of the article's first authors, and María Isabel Hernández-Alvarez, all three researchers at the IBUB and the IRSJD.

Sonia Fernández-Veledo, from the Institut d'Investigació Sanitària Pere Virgili (IISPV), the Universitat Rovira i Virgili and the CIBER Area of Diabetes and Associated Metabolic Diseases (CIBERDEM), also co-leads the study, which was conducted in collaboration with experts from other national and international institutions.

Protection against fat accumulation, inflammation and fibrosis

This chronic condition, which is caused not by alcohol consumption but by metabolic disturbances such as obesity, is characterised by excessive fat accumulation in the liver and can progress to more severe forms, such as advanced fibrosis or liver cancer.

To investigate the hepatic 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 through the plasma membrane of cells. The team therefore studied ENT1 expression-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 made it possible to establish a link between this transporter, nucleoside levels-particularly adenosine, a nucleoside involved in regulating inflammation and cellular responses to stress-and the development of the changes characteristic of 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. In addition, mice without ENT1 show better glucose tolerance and greater insulin sensitivity, suggesting that the effects of this transporter may extend beyond the liver and affect the body's overall metabolism.

A different role depending on the stage of the disease

The analysis of liver biopsies from patients and gene-expression databases has complemented the findings from animal models, showing that hepatic ENT1 expression varies throughout the course of MASLD. Expression is higher in the early stages (in both humans and mice), but decreases as the disease progresses. This suggests that the transporter is regulated differently depending on the stage of the condition.

«Higher ENT1 expression in the early stages could contribute to the transport and internalisation of adenosine in the liver, which would be consistent with the onset and early progression of the disease», the authors explain.

Patient data also strengthen the possibility that ENT1 is involved in the metabolism of the whole body. In people with early-stage MASLD, higher ENT1 expression in the liver is associated with higher insulin levels and a higher HOMA-IR index, an indicator of insulin resistance.

«Taken together, these results identify ENT1 as a regulator of systemic nucleoside metabolism and metabolic homeostasis, and highlight nucleoside transport as a previously underappreciated pathway contributing to the development and progression of MASLD», the researchers emphasise.

A therapeutic pathway with considerable potential

The findings of this study position this transporter as a potential target for exploring new therapeutic strategies. ENT1 is of particular interest because drugs capable of inhibiting its activity already exist, and some of these compounds are at different stages of clinical development. «Therefore, ENT1 is not an unknown pharmacological target, although its potential use in MASLD still requires considerably more research, particularly in humans and in larger cohorts», the researchers conclude.