Hepatic GPR110 plays a complex and context-dependent role in metabolic dysfunction-associated steatotic liver disease

Metabolically-dysfunction-associated steatotic liver disease (MASLD)—formerly known as nonalcoholic fatty liver disease (NAFLD) —is now the most common chronic liver disease worldwide, affecting more than 30% of the global population. Recent studies have documented seemingly contradictory roles for the G protein-coupled receptor 110 (GPR110, also known as ADGRF1) in male-biased models of MASLD. Here, we synthesize these findings and propose that such discrepancies do not invalidate the new discoveries but rather underscore the profound context‑dependency of GPR110 biology. We outline a multidimensional framework wherein the net effect of GPR110 signaling is dictated by sex hormones and their receptors, disease stage (simple steatosis vs . steatohepatitis/fibrosis), and the cell type-specific signaling plasticity of this G protein-coupled receptor. By critically appraising experimental designs, model limitations, incomplete hormonal characterization, and potential confounders, we highlight key considerations for translational research. Ultimately, we emphasize that precise, context-informed strategies will be critical for therapeutically targeting GPR110-mediated pathways across a heterogeneous patient population.