Levodopa and the dopamine receptor D1-Hippo/yes-associated protein axis: A novel therapeutic avenue for liver fibrosis

Abstract

Liver fibrosis remains a major global health challenge with limited therapeutic options. In their recent study, Wang et al report that levodopa, a dopamine precursor widely used in Parkinson’s disease, significantly attenuates carbon tetrachloride-induced liver fibrosis in rats by enhancing dopamine receptor D1 expression and activating the Hippo signaling pathway, leading to phosphorylation and inactivation of yes-associated protein 1. This discovery links G-protein-coupled receptor signaling to Hippo pathway regulation in hepatic fibrosis. The work highlights the dopamine receptor D1-Hippo/yes-associated protein 1 axis as a promising antifibrotic mechanism and introduces levodopa as a potential repurposing candidate for chronic liver disease. With its established safety and affordability, levodopa offers a rapidly translatable strategy that warrants validation in human tissues and diverse fibrosis models. Here, we place these findings in the broader context of G-protein-coupled receptor regulation of hepatic stellate cell activation, discuss translational opportunities for levodopa in liver fibrosis, and propose future directions to validate this pathway across disease models and clinical settings.

Key Words: Levodopa; Liver fibrosis; Dopamine receptor D1; Hippo signaling pathway; Yes-associated protein; Drug repurposing; Hepatic stellate cell; G-protein coupled receptor

Core Tip: This editorial highlights a novel mechanistic insight from a recent study by Wang et al, which identifies the dopamine precursor levodopa, a mainstay Parkinson’s disease therapy, as a potent inhibitor of liver fibrosis in experimental models. The antifibrotic effect is mediated through activation of dopamine receptor D1, which stimulates the Hippo signaling pathway to inactivate the profibrotic transcriptional coactivator yes-associated protein. With its decades-long clinical use, safety record, and affordability, levodopa offers translational advantages and positions this neurologic drug as a potentially rapid and cost-effective therapy for chronic liver disease.

INTRODUCTION

Liver fibrosis represents the final common pathway of most chronic liver injuries, including viral hepatitis, alcohol misuse, metabolic dysfunction-associated steatohepatitis, cholestatic liver disease, autoimmune hepatitis, and toxin-induced damage. Repeated cycles of hepatocellular injury, inflammation, and repair drive excessive extracellular matrix (ECM) deposition and architectural distortion. If unchecked, fibrosis progresses to cirrhosis, the principal cause of over one million deaths annually, accompanied by complications such as portal hypertension, ascites, variceal bleeding, and hepatocellular carcinoma[1,2]. The global burden is expected to rise in parallel with obesity, diabetes, and metabolic syndrome.

The approval of Resmetirom (Rezdiffra™), a selective thyroid hormone receptor-β agonist, represents a milestone in managing metabolic dysfunction-associated steatohepatitis[3]. However, it primarily improves steatosis and inflammation rather than directly targeting hepatic fibrosis, which remains the strongest predictor of clinical outcomes. Agents under development, including farnesoid X receptor agonist and peroxisome proliferator-activated receptors agonists, act mainly through metabolic and inflammatory modulation with limited direct antifibrotic effects. Therefore, new therapeutic strategies that address the core fibrogenic mechanisms are urgently needed.

Among potential pathways, G-protein-coupled receptors (GPCRs) are particularly attractive targets. They represent one of the largest receptor families and are modulated by over one-third of approved drugs. In the liver, GPCRs orchestrate diverse physiological processes, including glucose and lipid metabolism, bile acid synthesis, inflammation, vascular tone, and fibrogenesis. Despite their ubiquity, the contribution of GPCR signaling to hepatic fibrosis remains underexplored. In parallel, the Hippo/yes-associated protein (YAP) pathway has emerged as a key regulator of hepatic stellate cell (HSC) activation and tissue remodeling. Linking these two systems through the dopamine receptor D1 (DRD1)-Hippo/YAP axis introduces a new framework for antifibrotic therapy. Recently, Wang et al[4] provided the first direct evidence that levodopa, a dopamine precursor widely used in Parkinson’s disease, attenuates experimental liver fibrosis by restoring DRD1 expression and reactivating Hippo signaling, thereby suppressing YAP activity. This finding bridges neuropharmacology and hepatic fibrogenesis, suggesting that pharmacologic modulation of dopamine receptor signaling could be therapeutically repurposed for liver fibrosis.

CURRENT UNDERSTANDING OF FIBROGENESIS

Liver fibrosis is a dynamic process that balances tissue injury and repair. Unlike many organs, hepatic fibrosis can regress if the insult is removed, but persistent injury leads to irreversible progression to cirrhosis. HSCs are the principal mediators of fibrosis. In the healthy liver, quiescent HSCs store vitamin A in lipid droplets. Upon injury, they undergo transdifferentiation into contractile, proliferative, and ECM-producing myofibroblast-like cells[5]. Profibrotic cytokines, notably transforming growth factor-β (TGF-β), drive this activation through SMAD2/3 signaling[6], while platelet-derived growth factor, Wnt/β-catenin, and hedgehog pathways reinforce these fibrogenic programs[7-9]. The Hippo pathway is pivotal: When active, Hippo kinases phosphorylate YAP, preventing its nuclear translocation. Injury suppresses this activity, allowing YAP to enter the nucleus and promote transcription of profibrotic genes[10-13].

Fibrogenesis involves multiple hepatic cell types beyond HSCs. Hepatocytes are the initial targets of injury in most chronic liver diseases. Oxidative stress, lipotoxicity, and viral or metabolic insults cause hepatocyte death and release of damage-associated molecular patterns, which activate Kupffer cells and recruit infiltrating macrophages. These immune cells amplify inflammation and promote HSC activation through cytokines such as TGF-β, tumor necrosis factor-α, and interleukin-1β[14]. YAP signaling exhibits distinct, cell-type–specific roles: In hepatocytes, transient YAP activation supports compensatory proliferation and repair, whereas sustained activation leads to maladaptive regeneration, fibrosis, and tumorigenesis, contrasting with its predominantly profibrotic function in HSCs[15]. Additional drivers such as hypoxia, metabolic reprogramming, and matrix stiffness further sustain ECM accumulation. Single-cell analyses have revealed transcriptionally distinct HSC subsets with divergent fibrogenic and immunomodulatory functions[16], underscoring the need for cell-targeted strategies that account for intra-lineage heterogeneity. Given that YAP signaling and GPCR responsiveness may differ among these subsets, elucidating this diversity will refine DRD1-targeted antifibrotic approaches. Despite significant mechanistic insights, clinical translation remains challenging. Agents directly targeting TGF-β or platelet-derived growth factor signaling often fail due to toxicity or insufficient efficacy. Modulation of the Hippo/YAP pathway through GPCRs may offer a more selective and tolerable antifibrotic strategy.

GPCR-HIPPO/YAP CROSS-TALK IN LIVER FIBROSIS

GPCRs, the largest membrane receptor family, not only regulate metabolic and inflammatory pathways but also modulate Hippo/YAP signaling in a G-protein–specific manner[17]. Gαq/11 and Gα12/13 coupling generally activate YAP through actin remodeling, whereas Gαs-coupled receptors (such as DRD1 and β-adrenergic receptors) stimulate Hippo kinases, leading to YAP phosphorylation and cytoplasmic retention[18,19]. This mechanistic dichotomy allows selective pharmacologic modulation of YAP activity via GPCR signaling.

Dopamine receptors, traditionally studied in the central nervous system, are expressed in peripheral tissues including liver, kidney, and pancreas[20]. D1-like receptors (D1, D5) couple to Gαs, while D2-like receptors (D2-D4) couple to Gαi/o[21]. Dopamine receptor signaling has been implicated in fibrosis modulation: D2 receptor antagonism reduces inflammation and HSC activation[22,23], whereas D1 receptor activation suppresses YAP nuclear translocation and fibrogenic gene expression[24].

The hepatic dopamine system functions as a dynamic balance between D1-like and D2-like receptor signaling. Under physiological conditions, this equilibrium contributes to hepatic blood flow regulation, glucose metabolism, and immune tone. In chronic liver injury, alterations in dopamine synthesis or receptor expression may shift this balance toward dominant D2-like signaling, which enhances inflammation and fibrogenesis. Conversely, restoring D1-mediated Gαs-coupled signaling, such as through levodopa, reactivates Hippo kinase activity and suppresses YAP-driven transcription, providing a mechanistic basis for antifibrotic action.

Wang et al[4] confirmed that levodopa ameliorates CCl₄-induced fibrosis by increasing DRD1 expression, enhancing YAP phosphorylation, and reducing collagen deposition. This establishes the DRD1-Hippo/YAP axis as a central regulatory pathway in hepatic fibrosis and validates dopamine receptor signaling as a viable antifibrotic target. By linking a neurologic drug to hepatic GPCR-Hippo/YAP modulation, this study introduces a novel mechanism-based therapeutic paradigm (Table 1).

Table 1 Summary of G-protein-coupled receptor-Hippo/yes-associated protein signaling and therapeutic implications in liver fibrosis¹.

GPCR type/example	G-protein coupling	Effect on Hippo/YAP pathway	Representative receptor/agonist	Downstream impact on HSCs	Functional outcome	Therapeutic implication
Gαs-coupled GPCRs	Gαs	Activates MST1/2, LATS1/2, YAP phosphorylation and cytoplasmic retention	DRD1; β-adrenergic receptor	Inhibits HSC proliferation and ECM synthesis	Antifibrotic	Activation promotes Hippo signaling and suppresses fibrogenesis
Gαq/11-coupled GPCRs	Gαq/11	Inhibits LATS1/2, nuclear YAP activation	Angiotensin II receptor, endothelin receptor	Induces α-SMA and collagen expression	Profibrotic	Target for inhibition to attenuate YAP-driven fibrosis
Gα12/13-coupled GPCRs	Gα12/13	Activates RhoA-ROCK, suppresses Hippo, nuclear YAP activation	LPA receptor, S1P receptor	Promotes contractility and ECM deposition	Profibrotic	RhoA/ROCK inhibitors may synergize with DRD1 agonists
Gαi/o-coupled GPCRs	Gαi/o	Decreases cAMP, suppresses MST/LATS activity, enhances YAP nuclear localization	D2 dopamine receptor	Enhances inflammation and fibrosis	Profibrotic	Rebalancing D1/D2 signaling may restore antifibrotic tone
Levodopa (via DRD1 activation)	Gαs	Stimulates adenylate cyclase, increases cAMP, activates MST1/2-LATS1/2, promotes YAP phosphorylation and inactivation	Levodopa, dopamine, DRD1 activation	Suppresses HSC activation and ECM gene expression	Antifibrotic	Potential drug repurposing strategy to restore Hippo signaling and reduce fibrosis

¹Distinct G-protein-coupled receptor subclasses exert opposing regulatory effects on yes-associated protein activation depending on their G-protein coupling. Gαq/11-, Gα12/13-, and Gαi/o-linked receptors promote yes-associated protein activation and fibrosis, whereas Gαs-coupled receptors such as dopamine receptor D1 stimulate Hippo kinase activity and yes-associated protein phosphorylation, exerting antifibrotic effects. Levodopa, through dopamine receptor D1 activation, restores Hippo/yes-associated protein balance, suppresses hepatic stellate cell activation, and represents a promising drug repurposing candidate for liver fibrosis.

GPCR: G-protein-coupled receptor; YAP: Yes-associated protein; HSC: Hepatic stellate cell; MST1/2: Mammalian sterile 20-like kinase 1/2; LATS1/2: Large tumor suppressor 1/2; DRD1: Dopamine receptor D1; ECM: Extracellular matrix; α-SMA: Α-smooth muscle actin; RhoA: Ras homolog gene family member A; ROCK: Rho-associated coiled-coil containing protein kinase; LPA: Lysophosphatidic acid; S1P: Sphingosine-1-phosphate; cAMP: Cyclic adenosine monophosphate.

LEVODOPA AS A CANDIDATE ANTIFIBROTIC AGENT

Levodopa, the metabolic precursor of dopamine, has been the cornerstone of Parkinson’s disease treatment for over five decades[25]. Clinically, it is co-administered with carbidopa or benserazide to prolong systemic availability and minimize peripheral metabolism. Its pharmacology is well characterized, with a strong safety record extending across diverse populations[26,27]. Beyond the central nervous system, dopamine signaling participates in renal sodium handling, cardiovascular regulation, immune modulation, and gastrointestinal function[28,29], supporting its relevance to peripheral organs including the liver. Levodopa is rapidly absorbed in the small intestine and undergoes peripheral metabolism by aromatic L-amino acid decarboxylase and catechol-O-methyltransferase. Co-administration with carbidopa or benserazide enhances systemic bioavailability while reducing hepatic dopamine production. Notably, mild-to-moderate hepatic impairment does not significantly alter levodopa clearance, confirming its favorable hepatic safety profile[30-32].

In experimental fibrosis, levodopa restored DRD1-Hippo/YAP signaling and reduced collagen deposition[4]. Although the findings are compelling, they were derived from a single animal model. Further studies are needed to evaluate dose–response relationships, long-term efficacy, and cell-type specificity. As the hepatic dopamine system comprises both D1-like and D2-like receptors with opposing actions, the overall antifibrotic outcome may depend on their relative expression and activity. Chronic liver injury could disrupt this balance, favoring D2-dominant signaling that promotes fibrosis. Therapeutic restoration of D1-mediated signaling, either through levodopa or selective D1 agonists, may re-establish dopaminergic equilibrium. Early-phase translational studies should evaluate pharmacodynamic markers such as serum fibrosis indices, elastography-based stiffness, and YAP target gene expression in liver biopsies.

MECHANISTIC AND TRANSLATIONAL CONSIDERATIONS

A key aspect of DRD1-Hippo/YAP targeting is the cell-type specificity of its action. YAP signaling exhibits context-dependent roles: Transient activation supports hepatocyte regeneration, while sustained activation in HSCs drives fibrosis. Therefore, therapeutic modulation must selectively inhibit YAP in stellate cells without impairing hepatocyte regeneration. Preliminary data suggest DRD1 expression is enriched in activated HSCs but low in hepatocytes, implying that levodopa or DRD1 agonists may act primarily on fibrogenic cell populations. Single-cell and spatial transcriptomic analyses will be essential to confirm the cellular specificity of DRD1-mediated signaling and ensure both efficacy and safety. Recent single-cell studies identify distinct HSC subsets, myofibroblastic (ECM-producing) and cytokine-producing (immunomodulatory), with nonredundant roles in fibrosis[16]. Recognizing this intra-lineage heterogeneity is critical, as DRD1 agonists or YAP modulators may differentially affect these subsets. Integrating this knowledge could enable precision antifibrotic therapy tailored to specific HSC populations.

Compared with other antifibrotic approaches such as farnesoid X receptor agonists, peroxisome proliferator-activated receptors, and GLP-1 receptor agonists, targeting the DRD1-Hippo/YAP axis offers a more direct mechanism for suppressing fibrogenesis. While metabolic regulators primarily modulate inflammation and lipid metabolism, DRD1 activation directly inhibits HSC activation and ECM deposition. Given their distinct mechanisms, DRD1 agonists may complement metabolic regulators to achieve both metabolic and fibrotic improvement. Because levodopa’s human pharmacology and safety are well established, clinical proof-of-concept trials could feasibly assess antifibrotic efficacy using biomarkers such as enhanced liver fibrosis scores, magnetic resonance elastography stiffness, or transcriptional YAP targets.

CONCLUSION

Liver fibrosis remains a major unmet clinical need, with no approved antifibrotic therapy. The discovery that levodopa attenuates fibrosis via DRD1-Hippo/YAP signaling provides a compelling mechanistic and translational advance. Given levodopa’s established safety, low cost, and availability, clinical exploration in patients with early or moderate fibrosis appears feasible. Future studies should include pharmacokinetic evaluation, receptor profiling, and cell-type-specific analyses to optimize dosing and patient selection. Clarifying the hepatic D1/D2 receptor balance across disease stages will guide personalized strategies and enhance therapeutic precision. Pathway-based repurposing exemplified by levodopa may accelerate the translation of mechanistic discovery into clinical therapy, positioning the DRD1-Hippo/YAP axis as a potential paradigm shift in the treatment of liver fibrosis.