P4ha2, a subunit of prolyl-4-hydroxylases, contains a substrate binding and catalyzation domain and is a key enzyme in collagen synthesis. It is involved in multiple signaling pathways, such as the SAV1-mediated Hippo signaling pathway, PI3K/AKT signaling pathway, and Hedgehog (Hh) signaling pathway, and plays important roles in various biological processes and disease conditions [1,2,3,4,5].

In P4ha2-/-mice, the level of ductular reaction and fibrosis was significantly reduced compared with controls in DDC-induced chronic cholestasis, indicating that P4ha2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway [1]. In P4ha2-/-/MDR2-/-double knockout mice, decreased liver fibrosis and ductular reaction were observed compared with MDR2-/-mice, and cholangiocytes isolated from these double knockout mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition [1].

In conclusion, P4ha2 is crucial for collagen synthesis and is involved in multiple signaling pathways. Gene-knockout mouse models, especially P4ha2-/-and P4ha2-/-/MDR2-/-mice, have revealed its role in promoting hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases, highlighting its potential as a therapeutic target for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) [1].