Equilibrative nucleoside transporter 1 deficiency protects against diet-induced MASLD and is stage-associated in human liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to systemic metabolic disturbances, yet the early hepatic mechanisms contributing to disease initiation and progression remain incompletely understood. Alterations in nucleoside metabolism and signalling have been implicated in metabolic liver disease, but the role of nucleoside transport has not been defined. Here, we investigated the contribution of equilibrative nucleoside transporter 1 (ENT1), the predominant hepatic nucleoside transporter, to MASLD pathophysiology. By integrating human liver biopsies, public transcriptomic datasets, and diet-induced mouse models, including ENT1-deficient mice, we analysed ENT1 expression and its functional impact on hepatic and systemic metabolism. We show that hepatic ENT1 expression changes during MASLD, with increased expression at early disease stages in both humans and mice, followed by a decline with disease progression. Under basal conditions, ENT1 deficiency induces subtle metabolic alterations in the liver. Notably, loss of ENT1 decreases hepatic adenosine and is associated with protection against diet-induced steatosis, inflammation, and fibrosis, and with improved glucose tolerance and insulin sensitivity, potentially through systemic metabolic effects. In humans with MASLD, hepatic ENT1 expression correlates positively with insulin levels and HOMA-IR. Together, these findings identify ENT1 as a regulator of systemic nucleoside handling and metabolic homeostasis and highlight nucleoside transport as a previously underappreciated axis contributing to MASLD development and progression.