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

Abstract 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.