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Inhibition of Hippo/YAP signaling pathways by levodopa as novel therapeutic approaches for liver fibrosis. Jin-Bo Zhao1*, Gu-Qing Luo1*, Jia-Yun Lin1, Chi-Hao Zhang1, Guang-Bo Wu1, Hongjie Li1,Meng Luo1, Zheng-Hao Wu1#, Lei Zheng1# 1Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. *, # equal contribution. Abstract This commentary discusses a recently published article in the World Journal of Gastroenterology. Using a rat model of liver fibrosis induced by CCl4 Injection, the article confirms that Dopamine receptor D1 (DRD1) is closely associated with liver injury and the progression of liver fibrosis. To verify that the interaction between this receptor and the Yes-associated protein 1 (YAP1) signaling pathway plays a critical role in liver fibrosis, levodopa was administered in the CCl4 rat model to activate DRD1, which in turn inhibited the nuclear translocation of YAP1 protein. In previous studies, YAP1 has been shown to exert important functions in the process of liver injury repair. Therefore, the findings of this study demonstrate the interaction between DRD1, activated by levodopa treatment and the YAP1 signaling pathway, thereby providing evidence from animal experiments to support levodopa as a novel therapeutic strategy for liver fibrosis. Key Words: Dopamine receptor D1; Liver fibrosis; Yes-associated protein 1, CCl4 rat model, G protein-coupled receptors Core Tip: Based on the results of previous studies and preliminary experiments, this manuscript confirms a close association between the activation of DRD1 and the YAP1 signaling pathway. Notably, the nuclear translocation of YAP1 is a key mechanism for YAP1 to exert its biological functions. Activation of DRD1 by levodopa inhibits the nuclear translocation of YAP1, thereby alleviating liver injury and retarding the progression of liver fibrosis. TO THE EDITOR G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors encoded by the human genome and stand out as highly productive therapeutic targets—ligands targeting GPCRs represent over 30% of all clinically approved medications[1]. For fibrotic disorders, researchers have explored both GPCR inhibitors[2-5] and activators[6-8] to evaluate their therapeutic potential. Functionally, GPCRs interact with effector proteins associated with four major classes of G-proteins. Recent studies have clarified a key functional distinction: activation of GPCRs coupled to Gα12/13, Gαq/11, or Gαi/o subtypes promotes the nuclear translocation and transcriptional activity of YAP/TAZ; by contrast, GPCRs that couple to Gαs suppress YAP/TAZ nuclear localization and functional activity through increasing cyclic adenosine monophosphate (cAMP) levels[9]. Critically, GPCR expression exhibits significant heterogeneity—varying not only across different organs but also among adjacent cell types within the same tissue[10]. This expression pattern opens up the possibility of developing GPCR-directed therapies as a strategy for cell-selective inhibition of YAP/TAZ. Specifically, identifying and activating a GPCR that is selectively expressed on fibroblasts could provide a targeted approach: by inhibiting YAP/TAZ within the activated fibroblasts that drive disease progression, such a strategy could counteract multiple pro-fibrotic stimuli simultaneously. In the present study, researchers identified the dopamine receptor DRD1 as a fibroblast-selective target. When activated (via agonism), DRD1 inhibits YAP/TAZ-mediated fibroblast activation, reduces extracellular matrix (ECM) deposition and stiffening, and ultimately reverses experimental liver fibrosis. Biologically, DRD1 exhibits selective coupling to Gαs, a interaction that drives cAMP elevation[11]. This coupling enables DRD1 to counteract both mechanical and biochemical pro-fibrotic signals that otherwise promote fibroblast activation. Functionally, this translates to a key phenotypic shift in fibroblasts: DRD1 agonism effectively converts fibroblasts from a state that supports ECM deposition and tissue stiffening to one that favors ECM degradation and tissue softening. Against this research background, the administration of levodopa in CCl₄ rat model effectively activated DRD1, which was followed by the inhibition of YAP1 nuclear translocation. This sequence of events significantly suppressed the role of YAP1 in the progression of liver fibrosis. This promising finding provides an opportunity for the clinical application of this therapeutic target. MAIN FINDINGS OF THIS STUDY In this study, the administration of levodopa in CCl₄-induced rat model initially demonstrated alleviation of liver injury and liver fibrosis. Meanwhile, by reducing the dose of levodopa, the severe side effects of levodopa in the rat model treatment were partially avoided. Subsequently, experimental assays confirmed the significant activation of DRD1 and the inhibition of YAP1. Furthermore, through the detection of phosphorylated YAP1 (p-YAP1), the study elaborated on the detailed mechanism underlying the inhibition of the YAP1 signaling pathway. Combining the experimental results with the basic insights from previous studies, and by detailing the protein signaling pathway mechanism, this research revealed the critical mechanism of DRD1 activation in the progression of liver fibrosis. THE LIMITATIONS OF THIS STUDY The findings of this study are limited to CCl₄-induced rat model, which cannot fully encompass the comprehensive pathogenesis of liver fibrosis and cirrhosis[12-14]. Therefore, further studies using other models and human samples are required to validate the therapeutic role of DRD1 in the progression of liver fibrosis. Moreover, the expression of YAP1 exhibits cellular heterogeneity in the liver: YAP1 is expressed at non-negligible levels in cholangiocytes[15], endothelial cells, and hepatocytes, where it exerts critical functions, and changes in its expression during disease have also been extensively investigated. Notably, the functions and mechanisms of YAP1 in different cell types correspond to distinct pathological phenotypes, thereby exerting diverse physiological effects on the progression of liver fibrosis[16]. Furthermore, in studies on the role of the YAP1 protein in liver fibrosis, researchers have used verteporfin and metformin to inhibit the intrahepatic fibrotic process. Meanwhile, at the cellular level, in-depth investigations have been conducted into the function of the YAP1 protein in cholangiocytes and hepatic stellate cells[17]. Therefore, in future research, the cell type-specific localization of functionally active DRD1 should be precisely identified, which will facilitate a more accurate understanding of the therapeutic target responsible for its anti-fibrotic effects. CLINICAL SIGNIFICANCE OF THIS STUDY Despite the limitations, this study still holds significant clinical implications: Using levodopa (a DRD1 agonist), the researchers demonstrated that activation of this receptor in the liver and inhibition of YAP1 nuclear translocation could be achieved. Based on previous studies investigating the mechanism of YAP1 action in various liver cell types, YAP1 has been shown to accelerate the development and progression of liver diseases[16]. Although this study failed to specifically target and inhibit YAP1 function in a single specific liver cell type, comprehensive inhibition of intrahepatic YAP1 function may effectively alleviate disease progression. Collectively, these findings provide a potential and effective therapeutic target for the clinical treatment of liver fibrosis. CONCLUSION Currently, the mechanism by which DRD1 activation improves liver function in patients with chronic liver disease and liver fibrosis remains insufficiently understood. In-depth exploration of this underlying mechanism will provide a new direction for the clinical translation of DRD1 activation strategies. Furthermore, conducting clinical studies to evaluate the safety of DRD1 activation for liver fibrosis treatment, standardizing the manufacturing process of DRD1 agonists, and developing novel DRD1 activators will offer evidence to validate the clinical application of DRD1-based therapies. CONTRIBUTOR INFORMATION Jin-Bo Zhao,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Gu-Qing Luo,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Jia-Yun Lin,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Chi-Hao Zhang,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Guang-Bo Wu,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Hongjie Li,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Meng Luo, Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Zheng-Hao Wu,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Lei Zheng,Department of General Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.zl1055174020@163.com REFERENCES 1 Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. 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September 09, 2025, 11:13

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This study on the potential therapeutic effects of levodopa for liver fibrosis provides a novel perspective in the treatment of hepatic conditions, particularly in the context of liver injury induced by carbon tetrachloride (CCl4) in rats. The findings are promising, showing that levodopa not only reduces fibrosis markers like collagen deposition but also modulates key signaling pathways involved in liver regeneration. These results could pave the way for repurposing levodopa in treating liver diseases, especially given the lack of universally approved treatments for liver fibrosis.

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