A joint research team from JBNU School of Pharmacy and College of Medicine has identified a new molecular signaling mechanism that regulates the progression of liver fibrosis and suggested its potential as a therapeutic target.

JBNU announced on the 21st that the joint research team led by Professors 배은주 and 한창엽 of the School of Pharmacy and Professor 이창훈 of the College of Medicine demonstrated that a novel signaling axis from PAK4 (p21-activated kinase 4) to YAP (Yes-associated protein) promotes activation of hepatic stellate cells and the progression of fibrosis during liver fibrogenesis.

Liver fibrosis is a pathological condition in which extracellular matrix fibers such as collagen accumulate excessively in the liver due to repetitive chronic liver injury. If the disease progresses, it can develop into cirrhosis and liver cancer. The degree of fibrosis is considered a key factor determining prognosis in patients with chronic liver disease. However, effective therapies that suppress or reverse liver fibrosis itself remain limited, highlighting the need to identify molecular mechanisms that control disease progression and potential therapeutic targets.

Hepatic stellate cells are representative cells that drive the onset and progression of liver fibrosis. In a healthy liver they remain inactive and store vitamin A, but upon liver injury they become activated, proliferate, and produce fibrous matrix. The signaling networks that regulate hepatic stellate cell activation and cell fate are highly complex, and research continues to seek novel therapeutically targetable mechanisms.

The JBNU team focused on PAK4, a molecule primarily known as an anticancer target but recently found to have diverse functions including regulation of lipid and glucose metabolism. The results showed that PAK4 expression in hepatic stellate cells increases during liver fibrogenesis, and that this upregulation promotes activation and proliferation of hepatic stellate cells, playing an important role in fibrosis progression.

The researchers validated PAK4 function using a genetically modified mouse model in which PAK4 was selectively deleted in hepatic stellate cells. They also confirmed the potential for fibrosis improvement using a small-molecule selective PAK4 inhibitor. These experiments provide experimental evidence that therapeutic strategies targeting PAK4 can modulate the progression of liver fibrosis.

In particular, the team elucidated the specific molecular mechanism by which PAK4 promotes liver fibrosis. They found that PAK4 directly phosphorylates the transcriptional regulator YAP, which is involved in cell growth and tissue regeneration, thereby increasing YAP stability and its nuclear activity.

They also identified a previously unknown phosphorylation site on YAP. Based on these findings, the researchers proposed that the PAK4–YAP phosphorylation signaling axis is a core mechanism driving hepatic stellate cell activation and the progression of liver fibrosis.

The study was published in the latest issue of the international biochemistry and molecular biology journal Signal Transduction and Targeted Therapy (IF 81.2, JCR top 0.2%).

The first author, JBNU School of Pharmacy graduate student 김길환, said, "This study newly defines the role of PAK4 in liver fibrosis and is significant in that it reveals a novel YAP regulatory mechanism distinct from previously described inhibitory YAP phosphorylation."

Professor 한창엽 stated, "We have proposed the potential to develop new therapeutic strategies to control liver fibrosis and related diseases based on the PAK4–YAP signaling axis," and added, "We will concretize the development of therapeutic candidates and their clinical applicability through follow-up studies."

The study was led by JBNU School of Pharmacy with participation from multiple domestic and international collaborators. It was carried out with support from the National Research Foundation of Korea’s "Core Research Program and Bio·Medical Technology Development Program."