Background <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, yet efficient therapeutic approaches are lacking. The advent of glucagon-like peptide-1 receptor (GLP-1R)-based multi-target agonists generated renewed optimism for MASLD. Building on preclinical and clinical data suggesting synergistic metabolic benefits, we hypothesized that combining glucose-dependent insulinotropic polypeptide receptor (GIPR) or glucagon receptor (GCGR) agonism with GLP-1R agonism would confer superior protective effects against MASLD and its complications.</p> Methods <p>We identified genetic proxies of the effect of GLP-1R, GIPR, and GCGR by combining Mendelian randomization (MR), Bayesian colocalization, and linkage disequilibrium (LD) analyses. We then performed two-sample MR and colocalization analyses to estimate the causal effect of GLP-1R-based agonists on MASLD, its metabolic risk factors, and multi-organ complications.</p> Results <p>The MR analyses suggested genetically proxied GLP-1R-based agonists were causally associated with a reduced risk of MASLD (GIPR/GLP-1R agonist: OR: 0.17, 95%CI: 0.05–0.52, <i>P</i> = 2.07 × 10^− 3; GCGR/GLP-1R agonist: OR: 0.32, 95%CI: 0.20–0.52, <i>P</i> = 3.93 × 10^− 6; GCGR/GIPR/GLP-1R agonist: OR: 0.21, 95%CI: 0.08–0.56, <i>P</i> = 1.98 × 10^− 3), and these findings were well replicated in an independent cohort. Furthermore, these agonists also exhibited protective effects against liver cancer and cardiovascular diseases, as well as three metabolic risk factors, namely high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and insulin sensitivity index adjusted for BMI (ISI).</p> Conclusions <p>We identified the causal role of GLP-1R-based agonists in reducing the risk of MASLD and its complications, probably by improving systemic metabolic disorders and partly independent of their weight-loss effect.</p>