Reframing MASLD: Oxygen-Nutrient Imbalance as a Key Driver of Disease

In a new review, researchers reframe metabolic dysfunction-associated steatotic liver disease (MASLD) as a supply-demand injury in which excess portal caloric delivery can outpace hepatic oxygen compensation and drive near‑term progression risk in primary care populations. This perspective departs from lipid‑centric models by centering hepatic oxygenation and portal substrate load as primary injury drivers.

The proposed oxygen‑nutrient mismatch explains how high portal caloric flux overwhelms hepatocellular oxidative capacity, while compensatory hepatic arterial inflow fails to restore oxygen delivery. The review brings together cohort and physiologic data that link substrate overload and inadequate oxygen delivery to characteristic patterns of hepatocellular injury.

Recurrent systemic hypoxemia—most commonly from obstructive sleep apnea (OSA)—magnifies the mismatch and accelerates fibrosis. Screening for OSA and coordinating with sleep medicine offer modifiable targets to slow MASLD progression.

Emerging therapies that reduce hepatic caloric delivery or alter hepatic flow, such as resmetirom and obeticholic acid, show early promise. These agents act via weight reduction, thyroid‑receptor modulation, and effects on hepatic blood flow to address the substrate–oxygen imbalance.