Wang HY, Qi MM, Zhang K, Zhu YZ, Zhang J. Dopamine receptor D1-mediated suppression of liver fibrosis via Hippo/Yes-associated protein 1 signaling in levodopa treatment. World J Gastroenterol 2025; 31(34): 108617 [DOI: 10.3748/wjg.v31.i34.108617]
Corresponding Author of This Article
Jian Zhang, PhD, Professor, Department of Nuclear Medicine, Universal Medical Imaging Diagnostic Center, Shanghai University, No. 168 Changhai Road, YangPu District, Shanghai 200233, China. abiaoxp@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Sep 14, 2025; 31(34): 108617 Published online Sep 14, 2025. doi: 10.3748/wjg.v31.i34.108617
Dopamine receptor D1-mediated suppression of liver fibrosis via Hippo/Yes-associated protein 1 signaling in levodopa treatment
Hai-Yan Wang, Man-Man Qi, Kai Zhang, Yu-Zhao Zhu, Jian Zhang
Hai-Yan Wang, School of Medicine, Shanghai University Baoshan Campus, Shanghai 200444, China
Man-Man Qi, Kai Zhang, School of Medicine, Shanghai University, Shanghai 200444, China
Yu-Zhao Zhu, Shanghai Universal Medical Imaging Diagnostic Center, Shanghai 200233, China
Jian Zhang, Department of Nuclear Medicine, Universal Medical Imaging Diagnostic Center, Shanghai University, Shanghai 200233, China
Author contributions: Zhang J and Wang HY designed and performed the experiments, designed the figures and drafted the manuscript; Wang HY designed the experiments, analyzed the data, and critically revised the manuscript for important intellectual content; All authors read and approved the final manuscript; Zhang J and Wang HY confirm the authenticity of all the raw data.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Science and Technology Ethics Committee of Shanghai University (Ethical Review Consent No. ECSHU 2023-103).
Conflict-of-interest statement: The authors declare that they have no competing interests.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian Zhang, PhD, Professor, Department of Nuclear Medicine, Universal Medical Imaging Diagnostic Center, Shanghai University, No. 168 Changhai Road, YangPu District, Shanghai 200233, China. abiaoxp@163.com
Received: April 24, 2025 Revised: May 22, 2025 Accepted: August 13, 2025 Published online: September 14, 2025 Processing time: 135 Days and 18.5 Hours
Abstract
BACKGROUND
Yes-associated protein 1 (YAP1), a downstream transcriptional coactivator regulated by the Hippo signaling pathway, has been shown to be involved in liver fibrosis. YAP activity is modulated by G-protein coupled receptors, including Gα s-coupled protein dopamine receptor D1 (DRD1). Levodopa, a dopamine precursor, activates DRD1 on cell surface, triggering its downstream signaling pathway.
AIM
To investigate the therapeutic effect of levodopa and the downstream mechanism on carbon tetrachloride (CCl4)-induced liver fibrosis, including liver DRD1 expression.
METHODS
SD rats were intraperitoneally injected with 40% CCl4 for 8 weeks to induce liver fibrosis, followed by treatment with varying doses of levodopa for 2 weeks. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and liver pathology was assessed using hematoxylin and eosin and Masson's staining. Alpha-smooth muscle actin (α-SMA) content, along with the expressions of DRD1, YAP, and phosphorylated protein, was analyzed by Western blot, immunohistochemistry, and reverse transcription–quantitative real-time polymerase chain reaction.
RESULTS
Compared with the controls, levodopa-treated rats showed a decrease in the proportion of collagen in the liver and a recovery from liver fibrosis (P = 0.0007). Western blot and immunohistochemistry indicated that DRD1 was upregulated in the fibrotic liver of rats treated with levodopa, showing an increase in DRD1 Level (P < 0.0001). In addition, the upregulation of DRD1 activated the Hippo signaling pathway, manifested as increased YAP phosphorylation (P < 0.05).
CONCLUSION
This was the first study to demonstrate that levodopa attenuates CCl4-induced liver fibrosis by inhibiting the Hippo/YAP signaling pathways.
Core Tip: This study found that levodopa significantly alleviated carbon tetrachloride-induced liver fibrosis in rats by upregulating Gα s-coupled protein dopamine receptor D1 (DRD1) expression and enhancing Yes-associated protein 1 (YAP) phosphorylation through the activation of the Hippo signaling pathway. This study for the first time demonstrates levodopa's potential as a novel therapeutic strategy targeting the DRD1-Hippo/YAP axis in liver fibrosis.
