Beneficial Outcome Pathways: A New Mechanistic Framework to Map the Health Effects of Fasting in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Lifestyle interventions such as fasting are difficult to evaluate using placebo-controlled randomized trials, resulting in fragmented and heterogeneous evidence. The beneficial outcome pathways (BOPs) framework can address this limitation by integrating mechanistic data to clarify the causal processes leading to beneficial health outcomes, adapted from the adverse outcome pathway concept in toxicology. To illustrate the approach, we apply the BOP framework to fasting interventions for metabolic dysfunction-associated steatotic liver disease (MASLD). The initial trigger is an acute energy deficit that activates AMP-activated protein kinase (AMPK) signalling and inhibits mTORC1. Downstream key changes include the activation of autophagy and lipophagy, the suppression of de novo lipogenesis, the enhancement of fatty acid oxidation and ketogenesis, anti-inflammatory changes, and the restoration of hepatic and systemic insulin sensitivity. Overall, this new framework helps connect laboratory findings with clinical results and provides a clearer way to understand how fasting improves MASLD.