m⁶A‐Dependent ITIH1 Regulated by TGF‐β Acts as a Target for Hepatocellular Carcinoma Progression

Both the transforming growth factor beta (TGF-β) signaling pathway and N6-methyladenosine (m⁶A) modification for mRNA play an important role in hepatocellular carcinoma (HCC) progression. However, the relationship between TGF-β and m⁶A in hepatocellular carcinoma (HCC) remains unclear. Here, it is found that TGF-β can promote the liquid phase separation of METTL3, which further leads to the reduction of mRNA stability of ITIH1. As a secreted protein, ITIH1 can act as a ligand of integrin α5β1 to antagonize fibronectin, induce the inhibition of focal adhesion kinase signaling pathway, and inhibit the progression of HCC. In the preclinical model (mouse model, patient-derived organoid, patient-derived xenografts), purified recombinant ITIH1 (r-ITIH1) protein can be targeted for HCC. More importantly, r-ITIH1 can play a synergistic role in targeting HCC with TGF-β inhibitor. The downstream ITIH1 regulatory mechanism of TGF-β and m⁶A modification is revealed, and ITIH1 can be translational as a potential target for HCC.