Macrophage-specific deletion of plasminogen receptor Plg-RKT protects mice from high-fat diet-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), while hepatocyte deletion shows no protective effect. This cell-type specificity reveals macrophages as the critical cellular mediators of this receptor's metabolic impact. The protective mechanism involves reduced hepatic Akt signaling, decreased fatty acid synthesis, and enhanced PPARα-mediated fat oxidation, alongside a beneficial shift in adipose tissue macrophage polarization from inflammatory M1 to anti-inflammatory phenotypes. This finding challenges conventional understanding of MASLD pathogenesis by positioning immune cell plasminogen processing as a central driver rather than a secondary consequence. The work builds on emerging evidence that macrophage metabolic programming directly influences systemic energy homeostasis, extending beyond their traditional inflammatory roles. For adults struggling with metabolic syndrome, this suggests therapeutic targeting of macrophage plasminogen pathways could offer dual benefits: reducing liver fat accumulation while improving glucose control. However, the mouse model limitation and single-study nature require validation in human cohorts. The specificity for macrophages over hepatocytes makes this a particularly intriguing target for precision metabolic interventions.