ITIH4 Gene - Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 | Function, Mutations & Disease

ITIH4 encodes a heavy chain of the inter-alpha-trypsin inhibitor (ITI) family, a group of plasma serine protease inhibitors. The protein is synthesized primarily in the liver and secreted into the blood, where it acts as an acute-phase reactant. ITIH4 is involved in extracellular matrix stabilization, inflammation modulation, and cancer progression. Alternative splicing generates multiple isoforms, and the protein is often cleaved by kallikrein-related peptidases, generating fragments with distinct biological activities.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Inter-alpha-trypsin inhibitor (ITI) complex formation (Reactome: R-HSA-166786)

• Acute phase response signaling (KEGG: hsa04610)

• Complement and coagulation cascades (KEGG: hsa04610)

ITIH4 is a 120 kDa glycoprotein synthesized as a precursor and cleaved by furin to generate the mature heavy chain. It associates with bikunin (encoded by AMBP) to form the inter-alpha-trypsin inhibitor complex, which stabilizes the extracellular matrix by cross-linking hyaluronan. During inflammation, ITIH4 is upregulated and cleaved by kallikreins, releasing fragments (e.g., PK-120) that modulate neutrophil chemotaxis and vascular permeability. In cancer, ITIH4 expression is dysregulated, and its fragments serve as diagnostic or prognostic biomarkers. The protein contains a VIT domain and a C-terminal domain essential for complex assembly.