ORM2 (orosomucoid 2) is an acute-phase protein with multifaceted roles in metabolic, inflammatory, and immune regulation. As a hepatokine, ORM2 is induced by intermittent fasting through PPARα signaling and promotes adipose tissue browning via GP130/IL23R-p38 MAPK activation, leading to weight loss in obese mice 1. An obesity-associated ORM2 variant (D178E) shows impaired GP130/IL23R binding and reduced browning capacity, highlighting its therapeutic potential 1. ORM2 functions as an acute-phase reactant with context-dependent inflammatory effects. In rheumatoid arthritis, ORM2 is produced locally by synovial macrophages and fibroblast-like synoviocytes, promoting proinflammatory cytokine production (IL-6, TNF-α, IL-8, CCL2) via NF-κB and p38 MAPK pathways through glycophorin C receptor engagement 2. Conversely, astrocyte-derived ORM2 exerts anti-inflammatory effects by suppressing microglial activation and reducing neuroinflammation-associated cognitive deficits 3. In liver injury, cholangiocyte-derived ORM2 reprograms liver macrophages through an IP3R2-dependent calcium pathway, exacerbating ductular reactions and fibrosis 4. ORM2 also regulates lipid metabolism; TRIM24-mediated ORM2 upregulation alleviates hepatic steatosis and metabolic dysfunction in obstructive sleep apnea models 5. Additionally, elevated plasma ORM2 serves as a biomarker for prostate cancer diagnosis 6 and shows promise in monitoring liver diseases and fibrosis 7.