Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4)

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is an **abundant plasma protein produced by the liver** and belongs to the inter-alpha-trypsin inhibitor (ITI) family, which includes several heavy chain proteins. ITIH4 is **unique among ITIH proteins** as it is not covalently incorporated into bikunin-proteoglycan complexes, functioning independently in plasma. ITIH4 acts as a protease inhibitor via a novel mechanism: upon cleavage by certain serine proteases (such as MASP-1, MASP-2, and plasma kallikrein), it forms a noncovalent complex with the protease, sterically inhibiting substrate access without directly blocking the catalytic site. This system helps regulate **intravascular host defense, inflammatory responses, and extracellular matrix remodeling**. ITIH4 is rapidly cleaved and modulated in various diseases (inflammation, cancer, sepsis), often serving as an *acute phase biomarker*. While **ITIH4 is not currently considered an established therapeutic target** (enzyme, receptor, transporter), its unique mode of protease inhibition makes it of scientific interest for disease mechanisms and possible future drug development[1][2].

Other names

Inter-alpha-trypsin inhibitor heavy chain H470 kDa inter-alpha-trypsin inhibitor heavy chain H435 kDa inter-alpha-trypsin inhibitor heavy chain H4ITIH4IHRPITIHL1PK120PRO1851ITI heavy chain H4ITI-HC4Inter-alpha-inhibitor heavy chain 4Gp120PK-120H4PPlasma kallikrein-sensitive glycoprotein 120Plasma kallikrein-sensitive glycoproteinInter-alpha-trypsin inhibitor family heavy chain-related proteinInter-alpha-trypsin inhibitor heavy chain family member 4Inter-alpha-trypsin inhibitor, heavy chain-like, 1

Not a routine therapeutic target; potential for *development* of inhibitors or stabilizers due to protease inhibitory activity, but no approved drugs or mechanism-based therapies as of current scientific knowledge[1].