Orosomucoid 2 as an immunometabolic regulator in cardiometabolic disease: Molecular mechanisms and translational...

Cardiometabolic diseases are driven by persistent crosstalk between metabolic dysfunction and chronic low-grade inflammation. Orosomucoid 2 (ORM2), a highly glycosylated acute-phase protein of the α1-acid glycoprotein family, has conventionally been considered a circulating inflammatory marker. Recent evidence, however, suggests that ORM2 may also function as an active immunometabolic regulator linking hepatic stress responses, adipose tissue inflammation, macrophage polarization, and systemic metabolic homeostasis. This review summarizes the molecular characteristics, tissue distribution, glycosylation-dependent biology, and stress-responsive regulation of ORM2, with emphasis on cytokine-induced JAK/STAT and NF-κB signaling, hepatic and extrahepatic ORM2 expression, and potential glycoform-specific regulation. Macrophage polarization is discussed as a central mechanism through which ORM2 may modulate inflammatory resolution, adipose-liver communication, insulin sensitivity, vascular inflammation, and myocardial injury. Particular attention is given to the possibility that increased ORM2 may represent a compensatory response to inflammatory-metabolic stress rather than simply a marker of disease burden. The translational potential of ORM2 is also considered, including its possible use in multi-marker biomarker panels for cardiometabolic risk stratification and treatment monitoring. However, major limitations remain, including incomplete mechanistic knowledge, unclear receptor biology, limited data on ORM2 glycosylation in specific cardiometabolic phenotypes, assay standardization issues, and insufficient prospective clinical validation. In summary, ORM2 appears to be a biologically plausible mediator linking inflammation and metabolism, but further mechanistic and clinical studies are required to establish its causal role, biomarker value, and therapeutic potential in cardiometabolic disease.