From the brain to the liver: A pharmacokinetic dilemma and safety barriers in levodopa-based antifibrotic therapy

Abstract

Levodopa, a cornerstone therapy for Parkinson’s disease, has recently been reported to suppress hepatic stellate cell activation through the dopamine receptor D1 (DRD1)-Hippo/yes-associated protein (YAP) signaling axis, providing a novel mechanistic rationale for antifibrotic therapy in liver disease. However, its direct repurposing for peripheral organ indications faces a fundamental pharmacokinetic contradiction. Standard levodopa formulations are coadministered with peripheral aromatic L-amino acid decarboxylase inhibitors to minimize peripheral dopamine production, a strategy that may markedly limit the hepatic dopamine generation required for this antifibrotic effect. Moreover, nonselective dopamine receptor activation, potential impairment of liver regeneration via YAP inhibition, and possible adverse effects on portal hemodynamics represent critical translational challenges that warrant systematic evaluation. Future studies should prioritize the development of liver-targeted delivery systems or highly selective DRD1 agonist-based strategies to enable the safe and effective clinical translation of this mechanism.

Key Words: Levodopa; Liver fibrosis; Dopamine receptor D1; Drug repurposing; Pharmacokinetic mismatch

Core Tip: There is a lack of approved direct antifibrotic therapies for liver fibrosis. Levodopa has been reported to exert antifibrotic effects by activating hepatic dopamine receptor D1 (DRD1) and suppressing yes-associated protein signaling in hepatic stellate cells. However, its standard Parkinson’s disease regimen includes peripheral aromatic L-amino acid decarboxylase inhibitors, which limit the generation of the hepatic dopamine required for this mechanism. This opinion review highlights this pharmacokinetic contradiction and additional translational barriers, including receptor nonselectivity, regeneration-related safety concerns, and portal hypertension risk, and proposes liver-targeted or DRD1-selective strategies as more rational alternatives.

INTRODUCTION

Liver fibrosis remains a major unmet clinical challenge, as no approved therapies directly target fibrogenesis despite its central role in the progression to cirrhosis and hepatocellular carcinoma[1-7]. Emerging evidence indicates that dopaminergic signaling may regulate fibrogenic responses in peripheral tissues[8,9], while the Hippo/yes-associated protein (YAP) pathway has been widely implicated as a central driver of hepatic stellate cell (HSC) activation and fibrosis progression[3,10-15]. A recent study by Xie and Liu[16] proposed that levodopa exerts antifibrotic effects by activating dopamine receptor D1 (DRD1) and suppressing YAP signaling in HSCs, thereby linking dopaminergic signaling to the Hippo/YAP pathway[8,17,18]. This work further situates DRD1 within the broader framework of G protein-coupled receptor-mediated regulation of YAP activity, providing a compelling mechanistic rationale for targeting this axis in liver fibrosis[19]. Given its long-standing clinical use in Parkinson’s disease, levodopa has therefore been suggested as a promising candidate for antifibrotic therapy and exemplifies a potential drug repurposing strategy in liver disease[20,21].

However, this translational rationale raises a critical and insufficiently addressed question. In standard clinical practice, levodopa is almost invariably administered in combination with peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors to prevent dopamine production outside the central nervous system[22-24]. This pharmacological strategy, while essential for neurological efficacy, directly limits peripheral dopamine availability, including within the liver, and thus conflicts with the requirement for intrahepatic dopamine generation underlying the proposed antifibrotic mechanism. The clinical translation of this strategy is further constrained by receptor non-selectivity, potential impairment of hepatocyte regeneration due to YAP inhibition, and possible exacerbation of portal hypertension.

We argue that these conceptual and pharmacological inconsistencies fundamentally challenge the feasibility of directly repurposing levodopa for antifibrotic therapy. Instead, more rational strategies should focus on achieving precise intrahepatic DRD1 modulation, such as through targeted drug delivery or receptor-selective approaches.

THE CORE PHARMACOKINETIC CONTRADICTION: MUTUAL EXCLUSIVITY BETWEEN STANDARD THERAPY AND THE MECHANISM

Standard clinical levodopa therapy relies on the coadministration of peripheral AADC inhibitors, such as carbidopa or benserazide, which are systemically distributed and inhibit levodopa-to-dopamine conversion in peripheral organs, including the liver. This pharmacological property constitutes the mechanistic basis for reducing peripheral adverse effects in Parkinson’s disease patients. In contrast, the newly described antifibrotic mechanism relies on hepatic conversion of levodopa to dopamine via AADC, followed by activation of DRD1 on HSCs[17,18]. This represents a fundamental pharmacokinetic conflict: The clinical formulation is designed to inhibit hepatic biotransformation, whereas the antifibrotic mechanism requires it, as illustrated in Figure 1. Consequently, direct use of the standard combination regimen may render the antifibrotic effect ineffective because of insufficient intrahepatic dopamine generation, thereby introducing uncertainty regarding therapeutic efficacy. Conversely, levodopa monotherapy can expose patients to severe peripheral adverse effects that have led to its abandonment in routine clinical practice[22-24]. Importantly, the extent to which residual hepatic AADC activity persists under real-world clinical dosing remains insufficiently characterized. This conceptual “therapeutic mutual exclusivity” can therefore be reformulated as a testable hypothesis: Future studies should directly compare intrahepatic dopamine levels, DRD1 downstream signaling, or HSC activation markers in the presence vs absence of peripheral AADC inhibition.

Figure 1 Pharmacokinetic incompatibility between standard levodopa therapy and its proposed antifibrotic mechanism. Standard Parkinson’s disease treatment combines levodopa with peripheral aromatic L-amino acid decarboxylase inhibitors to limit peripheral dopamine synthesis, thereby restricting hepatic dopamine generation. In contrast, the proposed antifibrotic mechanism requires intrahepatic dopamine production, activation of dopamine receptor D1 on hepatic stellate cells (HSCs), and suppression of Hippo/yes-associated protein signaling, resulting in HSC inactivation. This mismatch illustrates a fundamental pharmacokinetic dilemma for translational application. PD: Parkinson’s disease; AADC: Aromatic L-amino acid decarboxylase; HSC: Hepatic stellate cell; DRD1: Dopamine receptor D1; YAP: Yes-associated protein.

BEYOND PHARMACOKINETICS: MULTILEVEL SAFETY BARRIERS TO CLINICAL TRANSLATION

Even if the pharmacokinetic barrier is overcome, several critical safety challenges remain. The first issue is receptor selectivity. Dopamine functions as a nonselective ligand capable of activating both DRD1 and DRD2[8,17]. Xie and Liu[16] reported that D1 receptors exert antifibrotic effects, whereas D2 receptors promote fibrosis and inflammation[25-27]; however, dopamine receptor expression patterns and downstream coupling may be pathologically remodeled in chronically inflamed livers. Concurrent activation of D2-dominant signaling could attenuate or even counteract the anticipated benefits of DRD1 engagement. This mechanistic consideration provides a plausible explanation for potential therapeutic failure. Thus, highly selective DRD1 agonists or liver-targeted delivery strategies represent more rational translational approaches.

The second issue is the “regeneration paradox” of YAP signaling. While YAP inhibition suppresses HSC activation, YAP is also a central regulator of hepatocyte proliferation and liver regeneration[28-30]. Systemic YAP inhibition may therefore compromise the regenerative capacity of patients with advanced or decompensated liver disease, potentially accelerating liver failure. Therefore, the potential tension lies not in YAP inhibition per se, but in the opposing requirements of different hepatic cell populations. Future studies incorporating cell type-specific modulation (HSC-specific and hepatocyte-specific effects) and stratification by disease stage (compensated vs decompensated cirrhosis) will be necessary to define a therapeutic window in which antifibrotic efficacy can be achieved without compromising regenerative capacity.

Finally, the potential risk of exacerbating portal hypertension warrants serious consideration. Central hemodynamic concern lies in drug-induced splanchnic vasodilation, a well-established effect of dopaminergic signaling and DRD1 activation[31,32]. In cirrhotic patients with established portal hypertension, enhanced splanchnic vasodilation may increase portal venous inflow and pressure, thereby increasing the risk of life-threatening complications, such as variceal bleeding. Importantly, this specific hemodynamic liability cannot be adequately captured in standard fibrosis models that lack portal hypertension. Rigorous evaluation in preclinical models incorporating clinically relevant portal hypertensive features is essential before any consideration of clinical translation, including direct measurements, such as the hepatic venous pressure gradient[33-35].

FUTURE DIRECTIONS AND TRANSLATIONAL PERSPECTIVES

Future research should adopt a staged and translationally oriented strategy to bridge current mechanistic insights with clinical applicability. In the short term, efforts should prioritize pharmacological optimization and targeted delivery strategies. The development of peripheral-restricted or liver-enriched DRD1 agonists represents a rational approach to enhance antifibrotic efficacy while minimizing systemic dopaminergic effects and receptor non-selectivity[36]. In parallel, delivery systems targeting hepatocytes and HSCs, including nanoparticle-based platforms[37-41], offer a promising approach to enhance cellular specificity and intrahepatic drug accumulation while minimizing off-target exposure[42,43]. Such approaches may help reconcile the competing demands of efficacy and safety that currently limit translational potential.

In the longer term, advances in spatially resolved and systems-level technologies will be essential to refine therapeutic strategies. Spatial multiomics approaches should be employed to comprehensively map dopamine receptor expression patterns, downstream signaling networks, and cellular heterogeneity across different stages of human liver disease[44-46]. These data will provide critical insights into disease stage-specific therapeutic responsiveness and may guide precision targeting of dopaminergic pathways[47,48]. Furthermore, candidate therapeutic strategies must be systematically evaluated in preclinical models that more accurately recapitulate human disease complexity, particularly those incorporating portal hypertension and impaired regenerative capacity[49-52]. Such models are essential to assess not only antifibrotic efficacy but also the integrated effects on hepatic regeneration and splanchnic hemodynamics[53,54]. This is particularly important given the potential for dopaminergic signaling to influence vascular tone and portal pressure.

Collectively, a coordinated framework integrating targeted pharmacology, advanced omics technologies, and disease-relevant modeling will be required to enable the safe and effective clinical translation of dopaminergic antifibrotic strategies, as summarized in Figure 2.

Figure 2 Future translational strategies toward precision antifibrotic therapy. The schematic summarizes three complementary domains. Precision therapeutics include hepatic stellate cell (HSC)-targeted delivery systems, such as nanoparticle-based levodopa prodrugs, and the development of peripherally restricted or highly selective dopamine receptor D1 modulators to minimize off-target receptor activation. Comprehensive evaluation emphasizes spatial multi-omics mapping of dopamine receptor D1 and dopamine receptor D2 expression across stages of liver disease, together with systematic assessment of portal hemodynamics and liver regeneration. Clinical goals focus on achieving effective antifibrotic efficacy through HSC inactivation while preserving hepatocyte regenerative capacity and ensuring yes-associated protein signaling safety, alongside maintenance of stable portal hemodynamics. HSC: Hepatic stellate cell; DRD: Dopamine receptor D; YAP: Yes-associated protein.

CONCLUSION

The identification of levodopa-mediated suppression of liver fibrosis via the DRD1 Hippo/YAP axis represents an important conceptual advance. However, as discussed above, a fundamental pharmacokinetic misalignment exists between current clinical levodopa formulations and the requirement for intrahepatic dopamine generation. This discrepancy, conceptualized here as “therapeutic mutual exclusivity,” is further compounded by receptor non-selectivity, potential impairment of hepatic regeneration, and hemodynamic risks related to portal hypertension. These limitations do not negate the therapeutic potential of dopaminergic signaling, but rather redefine the conditions under which it may be clinically applicable[55]. Future research should therefore move beyond levodopa itself. In the short term, efforts should focus on developing peripheral-restricted or liver-enriched DRD1 agonists[56]. In parallel, hepatocyte- and HSC-targeted delivery systems, including nanoparticle-based approaches, may enhance cellular specificity while minimizing off-target exposure[57]. In the longer term, spatial multiomics approaches should be employed to map dopamine receptor expression across stages of human liver disease[58], and candidate strategies should be systematically evaluated in preclinical models incorporating portal hypertension to comprehensively assess effects on liver regeneration and hemodynamics[59]. Such a shift from direct drug repurposing to mechanism-aligned therapeutic design may ultimately determine whether dopaminergic modulation can be successfully translated into a viable antifibrotic strategy[60,61].