△Schematic illustration explaining the role of PDE4D as a stage-specific therapeutic target in liver fibrosis and the mechanism by which an allosteric inhibitor regulates fibrosis

 Professor Jeonghan Kim (co–corresponding author) of the Department of Biochemistry, College of Medicine, The Catholic University of Korea, and Dr. Jay H. Chung (co–corresponding author) of the National Institutes of Health (NIH) in the United States, together with their international joint research team, have identified a therapeutic target that can dramatically suppress liver fibrosis. This discovery presents a new treatment strategy that may overcome liver fibrosis, long regarded as one of the greatest challenges in liver disease therapy.
 With the rapid rise in the prevalence of obesity and metabolic diseases in recent years, the number of patients with early-to-moderate liver fibrosis associated with metabolic inflammation has also been steadily increasing. Liver fibrosis refers to a condition in which scar tissue (fibrotic tissue) accumulates excessively in the liver as various liver diseases—such as fatty liver disease, chronic viral hepatitis, alcoholic liver disease, and metabolic dysfunction–associated steatohepatitis—worsen.
 In the early stages of liver fibrosis, substantial recovery toward a near-normal liver can be achieved if causal treatments—such as weight reduction, improvement of insulin resistance, and viral suppression—are implemented. However, if fibrosis persists and progresses to cirrhosis, the tissue becomes irreversibly altered, posing a serious threat to life. Since no effective anti-fibrotic drug has been proven to date and liver transplantation remains the only treatment option, identifying therapeutic targets that act specifically at the fibrosis stage and developing targeted therapies accordingly have been recognized as core goals for liver disease treatment strategies.
 Professor Kim focused on the observation that the enzyme PDE4D (phosphodiesterase 4D) increases abnormally during the liver fibrosis stage, based on transcriptomic analyses across disease stages in patients with liver disorders. PDE4 enzymes degrade intracellular cyclic adenosine monophosphate (cAMP) and have long been highlighted as important regulatory factors in inflammatory and fibrotic diseases. Although drugs broadly inhibiting PDE4 enzymes have shown efficacy in various animal studies, severe side effects such as nausea and vomiting in humans have hindered their practical use.
 After precise analysis of individual PDE4 isoforms, the research team discovered that the “long isoform” of PDE4D becomes particularly elevated during the fibrotic process. An isoform refers to a protein variant derived from the same gene but with slightly different functions.
 Notably, this long isoform increases markedly when hepatic stellate cells—the key cells that drive liver fibrosis—become activated, and it functions like a “switch” that simultaneously promotes collagen production (fibrotic tissue formation), inflammatory signaling, and cell migration. In other words, the study identified PDE4D long isoform as a central hub that drives both inflammation and fibrosis in liver tissue. This is significant because it goes beyond suppressing fibrosis alone and instead identifies a precision target that regulates fibrosis and inflammation together.
 Building on this finding, the research team conducted a collaborative study with the NIH and Cedars-Sinai Medical Center, proposing an allosteric inhibitor that selectively suppresses only the PDE4D long isoform as a potential therapeutic candidate for liver fibrosis. Allosteric inhibitors bind to specific regulatory sites (allosteric sites) rather than the active site of a protein, inducing structural changes that allow for selective and precise inhibition. This structural and mechanistic approach offers a possible solution to the side-effect issues associated with conventional pan-PDE4 inhibitors.
 Professor Kim stated, “Advanced liver fibrosis is extremely difficult to reverse, but through this study, we identified PDE4D—which increases selectively during the fibrosis stage—as a new therapeutic target, and we preclinically demonstrated that an allosteric inhibitor targeting this enzyme can simultaneously reduce fibrosis and inflammation.” He further noted, “We will continue follow-up development so that this target and candidate molecule can be developed into a precision-medicine–based therapy for liver fibrosis and eventually become a next-generation anti-fibrotic drug used in real clinical practice.”
 This study was conducted as an international research collaboration between the College of Medicine, The Catholic University of Korea, and the U.S. National Institutes of Health, with support from the National Research Foundation of Korea’s Excellent Young Researcher Program, First-Move Laboratory Program, and Basic Research Laboratory (BRL) Program. The findings were published in the latest issue of the prestigious medical journal Journal of Clinical Investigation.

△Professor Jeonghan Kim and Dr. Jay H. Chung