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ResearchIn-Press PreviewHepatologyInflammation Open Access | 10.1172/JCI182571

Selective inhibition of long isoforms of phosphodiesterase 4D mitigates liver fibrosis in mouse models

Jeonghan Kim,1 Heeeun Yoon,2 Seoung Chan Joe,1 Antoine Smith,2 Jinsung Park,2 Geunhye Hong,1 Ji Myeong Ha,1 Eun Bae Kim,1 Ekihiro Seki,3 Myung K. Kim,2 Hae-Ock Lee,4 Ho-Shik Kim,1 and Jay H. Chung2

1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

Find articles by Kim, E. in: PubMed | Google Scholar

1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

Find articles by Kim, M. in: PubMed | Google Scholar

1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

Find articles by Lee, H. in: PubMed | Google Scholar

1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

Find articles by Kim, H. in: PubMed | Google Scholar

1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

2Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, United States of America

3Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

4Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Korea, Republic of

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Published November 6, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI182571.
Copyright © 2025, Kim et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 6, 2025 - Version history
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Abstract

Chronic inflammation leads to tissue fibrosis which can disrupt the function of the parenchyma of the organ and ultimately lead to organ failure. The most prevalent form of this occurs in chronic hepatitis which leads to liver fibrosis and, ultimately, cirrhosis and hepatic failure. Although there is no specific treatment for fibrosis, the phosphodiesterase 4 (PDE4) competitive inhibitors have been shown to ameliorate fibrosis in rodent models. However, competitive inhibitors of PDE4 have shown significantly reduced effectiveness due to severe gastrointestinal side effects. The PDE4 family is composed of four genes (PDE4A–D) with each having up to 9 differentially spliced isoforms. Here, we report that PDE4D expression is specifically elevated during the hepatic fibrosis stage of liver disease progression. Furthermore, the expression of the long isoforms of PDE4D is selectively elevated in activated hepatic stellate cells, leading to the enhanced accumulation of extracellular matrix components. In a mouse model of liver fibrosis, genetic ablation of PDE4D or pharmacological inhibition using D159687, a selective allosteric inhibitor targeting the long isoforms of PDE4D, suppresses the expression of inflammatory and profibrogenic genes. These findings establish the long isoforms of PDE4D as key drivers of liver fibrosis and highlight their potential as therapeutic targets to ameliorate liver fibrosis.

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