ITIH2 (inter-alpha-trypsin inhibitor heavy chain 2) is a serum and extracellular matrix protein that functions as a hyaluronan-binding carrier protein regulating hyaluronan localization, synthesis, and degradation 1. In cancer biology, ITIH2 is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1 in mesenchymal-like lung cancer cells, and its depletion reduces hyaluronan matrix formation and cancer cell migration and invasion 1. In hepatocellular carcinoma, tumor-derived ITIH2 promotes angiogenesis by activating the PI3K/AKT signaling pathway in vascular endothelial cells through THBS1 ubiquitination-dependent regulation, without directly affecting tumor cell proliferation 2. ITIH2 demonstrates clinical significance as a disease biomarker across multiple conditions: it associates with COVID-19 severity as an early predictor 3, serves as a component of diagnostic signatures for pancreatic ductal adenocarcinoma detection 4, correlates with systemic lupus erythematosus disease activity and renal damage 5, and is more abundant in severe COVID-19 survivors compared to non-survivors 6. Additionally, ITIH2 undergoes aging-associated structural changes in cerebrospinal fluid that associate with neurodegeneration-related clinical features 7, and is present in plasma-derived extracellular vesicles of hepatocellular carcinoma patients 8. These findings establish ITIH2 as a multifunctional extracellular protein with roles in tumor progression, immune homeostasis, and disease monitoring.