ITIH4 (inter-alpha-trypsin inhibitor heavy chain 4) is a Type II acute-phase protein involved in inflammatory responses and extracellular matrix stabilization. ITIH4 functions as an endopeptidase inhibitor that responds to cytokine signaling, particularly IL-6, which positively regulates its expression 1. The protein is upregulated during acute inflammatory states, including H. pylori infection-induced gastric inflammation 1, and serves as a diagnostic biomarker for neurosyphilis in cerebrospinal fluid alongside inflammatory pathway activation 2. ITIH4 has emerging roles in vascular and pulmonary diseases. It is expressed by smooth muscle cells in atherosclerotic plaques, with genetic associations to coronary artery disease 3. In chr3 obstructive pulmonary disease and emphysema, ITIH4 deficiency exacerbates oxidative stress-induced apoptosis in airway epithelial cells through JNK-dependent signaling 4. The protein exhibits cytoprotective functions through extracellular mechanisms, protecting cells from oxidative damage and particulate matter exposure 4. Genetically, ITIH4 polymorphisms associate with infant rapid weight gain 5, depressive symptoms during pregnancy 6, and reduced viral control in HIV-1 infection 7. ITIH4 participates in psychoneuroimmunological signaling relevant to well-being modulation 8. These findings suggest ITIH4 functions as both an acute-phase inflammatory mediator and a protective factor against cellular stress in multiple disease contexts.