ITIH3 (inter-alpha-trypsin inhibitor heavy chain 3) is a plasma protein that functions as a carrier and binding protein for hyaluronan in the extracellular matrix, regulating hyaluronan localization, synthesis, and degradation [UniProt]. The protein exhibits endopeptidase inhibitor activity and is present in extracellular exosomes and platelet dense granules [GO Annotations]. Genetically, ITIH3 variants are associated with multiple disease states. ITIH3 was identified as a causal locus for depression risk through Mendelian randomization and summary-data-based analysis 1. In cardiovascular pathophysiology, ITIH3 is an inflammatory protein with causal effects on heart failure development 2. ITIH4 SNP rs2239547 was significantly associated with reduced risk of depressive symptoms during pregnancy, with a specific GCCT haplotype showing positive association 3. Clinically, ITIH3 serves as a potential disease activity biomarker in myasthenia gravis, with serum levels correlating with disease activity scores and localizing at neuromuscular endplates 4. In hepatic metabolism, ITIH3 functions as a hepatokine that protects against non-alcoholic fatty liver disease by downregulating mitochondrial respiration and de novo lipogenesis 5. ITIH3 is also a component of diagnostic biomarker panels for epithelial ovarian cancer 6 and elevated expression associates with poor prognosis and metastatic potential in gastric cancer 7.