Progesterone receptor membrane component 1 accelerates liver fibrosis by interacting with transforming growth factor...

Transforming growth factor-beta (TGF-β) is a central driver of hepatic stellate cell (HSC) activation via SMAD signaling, ultimately contributing to liver fibrosis and cirrhosis. While progesterone receptor membrane component 1 (Pgrmc1), a non-canonical progesterone receptor, has been implicated in liver metabolism, its role in liver fibrosis remains poorly understood.

To investigate the involvement of PGRMC1 in liver fibrosis, we analyzed public Gene Expression Omnibus (GEO) datasets from cirrhotic patients. A carbon tetrachloride (CCl₄)-induced liver fibrosis model was established in wild-type and Pgrmc1-knockout (KO) mice. Additionally, primary hepatocytes and Lx-2 cells were used to explore cell-type specific signaling pathways.

Public dataset analysis revealed that higher PGRMC1 expression is associated with cirrhosis development and shorter survival in cirrhotic patients. In a CCl₄-induced model, Pgrmc1-KO mice exhibited significant resistance to liver fibrosis with suppression of TGF-β signaling. However, Pgrmc1-KO primary hepatocytes were prone to CCl₄-induced apoptosis. Instead, PGRMC1 knockdown significantly reduced TGF-β receptor (TGF-βR) protein levels and SMAD phosphorylation. Inhibition of TGF-βR1 abrogated the reduction in SMAD phosphorylation observed in PGRMC1-knockdown cells and co-immunoprecipitation assay revealed the interaction between PGRMC1 and TGF-βR.

Collectively, our findings demonstrate that PGRMC1 plays a crucial role in liver fibrosis progression by regulating TGF-βR, highlighting its potential as a promising therapeutic target for antibody-based treatment.