ITIH1 (inter-alpha-trypsin inhibitor heavy chain 1) is a secreted extracellular protein that functions as a broad-spectrum immune modulator and tumor suppressor. As a ligand of integrin α5β1, ITIH1 antagonizes fibronectin and inhibits focal adhesion kinase signaling 1. The protein exhibits protease inhibitory activity and contains carbohydrate and hyaluronic acid binding domains, suggesting roles in extracellular matrix organization [GO annotations]. In hepatocellular carcinoma (HCC), ITIH1 acts as a tumor suppressor through multiple regulatory mechanisms. TGF-β signaling reduces ITIH1 mRNA stability via METTL3-mediated m6A modifications 1, while lysine demethylase 5C (KDM5C) epigenetically silences ITIH1 transcription, activating PI3K/AKT oncogenic signaling 2. Notably, ITIH1 expression is substantially decreased in HCC tissues and inversely correlates with patient prognosis 3. Recombinant ITIH1 protein demonstrates therapeutic potential, synergizing with TGF-β inhibitors in preclinical HCC models 1. Beyond HCC, ITIH1 emerges as a protective factor in degenerative diseases. Mendelian randomization studies identify ITIH1 as a causal therapeutic target for hip osteoarthritis 4 and as a tier-2 drug target for kidney stone prevention, where genetic overexpression is negatively correlated with disease risk 5. ITIH1 also associates with depression risk in proteome-wide association studies 6. The protein was upregulated in pediatric metabolic dysfunction-associated steatotic liver disease 7, suggesting context-dependent disease involvement.