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

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.