A Narrative Review of the Multi-Target Mechanisms of Glabridin in Skin Lightening

Abstract

Background

Hyperpigmentation disorders are a leading cause of dermatological consultation worldwide. Conventional depigmenting agents such as hydroquinone and kojic acid primarily target tyrosinase, but their efficacy is limited by safety concerns and single-mechanism action. There is growing interest in natural multi-target compounds that modulate melanogenesis through complementary pathways.

Objective

This review summarizes the diverse molecular mechanisms through which glabridin, a prenylated isoflavan from Glycyrrhiza glabra root, exerts skin-lightening effects.

Methods

A comprehensive literature search was conducted in PubMed and Web of Science. Studies reporting the effects of glabridin on melanogenesis, inflammation, melanosome transfer, and melanosome degradation were evaluated.

Results

Glabridin inhibits tyrosinase activity and regulates melanogenic gene transcription. It also suppresses NF-κB-mediated inflammation, inhibits melanosome transfer through suppression of dendritic elongation, and promotes autophagy-mediated melanosome degradation. Additionally, this review addresses pharmacokinetic limitations, particularly poor aqueous solubility and bioavailability, and discusses formulation strategies designed to overcome them.

Conclusion

Glabridin is a multi-target depigmenting agent that exerts skin-lightening effects through modulation of multiple nodes within the melanogenesis cascade, while maintaining an improved safety profile. This review provides an integrated perspective on the diverse biological activities of glabridin, bridging mechanistic insights with formulation advances to highlight its therapeutic potential in depigmentation. Further clinical trials are warranted to establish its therapeutic role in hyperpigmentation disorders.

Introduction

Skin pigmentation is a complex biological process governed by melanogenesis. Melanocytes produce melanin pigments within specialized organelles called melanosomes.^1,2 Melanin serves essential photoprotective functions against ultraviolet (UV) radiation-induced damage.³ However, aberrant melanin production leads to hyperpigmentation disorders, including melasma, post-inflammatory hyperpigmentation (PIH), solar lentigines, and age spots. These disorders represent a leading cause of dermatological consultation worldwide.^4,5

Hyperpigmentation disorders disproportionately affect individuals with Fitzpatrick skin types III–VI, and the visible nature of these conditions imposes a significant psychologic burden, adversely affecting quality of life, self-esteem, and social functioning. Post-inflammatory hyperpigmentation (PIH) is among the most prevalent pigmentary disorders; the prevalence of PIH due to acne vulgaris has been reported to be 65%, 48%, and 25% for African American, Hispanic, and Caucasian patients, respectively.⁶ Melasma, another highly prevalent condition, predominantly affects women of reproductive age, particularly those of East and Southeast Asian, African, and Latin American descent. Despite the availability of multiple therapeutic options, ranging from topical agents and chemical peels to laser and energy-based devices, current treatments yield unsatisfactory outcomes.⁷ A recent systematic review reported complete response rates of only 5.4% with topical therapies, 18.1% with laser and energy-based devices, and 2.4% with combination therapies in PIH patients. Moreover, adverse events such as retinoid dermatitis and paradoxical worsening of pigmentation have been reported, further limiting treatment tolerability.⁸ The chronic, relapsing nature of hyperpigmentation disorders, combined with the lack of a gold standard therapy and suboptimal clinical outcomes, underscores a substantial unmet need in both dermatological and cosmetic applications.⁹

Conventional depigmenting agents have focused predominantly on tyrosinase inhibition. This copper-containing enzyme catalyzes the rate-limiting step in melanin biosynthesis: the hydroxylation of L-tyrosine to L-DOPA and subsequent oxidation to dopaquinone.^10–12 Hydroquinone, the well-established depigmenting agent, inhibits tyrosinase effectively. However, it is associated with significant adverse effects, including irritant dermatitis, exogenous ochronosis, and potential mutagenicity.¹³ Alternative agents such as kojic acid,¹⁴ arbutin,¹⁵ and ascorbic acid derivatives¹⁶ offer improved safety profiles. Nevertheless, they often demonstrate limited efficacy compared with hydroquinone.

Currently, dermatological research has shifted from traditional single-target approaches toward multi-target strategies. These strategies address multiple nodes in the melanogenesis network.¹⁷ It is well known that melanogenesis is regulated by a signaling network. This network involves transcriptional, post-translational, inflammatory, and intercellular communication mechanisms.¹⁸ An ideal depigmenting agent would therefore engage multiple targets across this network. Such an approach could achieve superior efficacy while reducing the risk of compensatory upregulation.

Glabridin, a prenylated isoflavan from Glycyrrhiza glabra root extract, has been identified as a depigmenting agent with diverse biological activities.^19,20 Yokota et al characterised its tyrosinase-inhibitory activity in 1998.²¹ Subsequent investigations have revealed a range of pharmacological activities relevant to melanogenesis regulation. These include direct enzymatic inhibition of tyrosinase^22,23 and transcriptional suppression of melanogenic gene expression via MITF-related pathways.^24,25 The compound also exerts anti-inflammatory effects through NF-κB and MAPK pathway modulation.^26–32 Additionally, glabridin regulates melanosome transfer and degradation activities.^33–35

This review integrates evidence from in vitro, in vivo, and clinical studies to summarize how glabridin modulates multiple pigmentation pathways. The pharmacokinetic challenges that limit its clinical translation and current formulation strategies are also evaluated. Previous reviews of glabridin have provided valuable overviews of its phytochemical characterization and broad pharmacological activities, including anti-inflammatory, antioxidant, and anti-tumor properties, but have treated its skin-lightening activity only as one of many general bioactivities without dedicated mechanistic analysis.^19,20 In addition, although previous reviews have addressed skin-lightening strategies from broader perspectives—including reviews of depigmenting ingredients, adverse effects, and public health implications of cosmetic skin lightening—no review has focused specifically on glabridin as a multi-target depigmenting agent within the melanogenesis cascade.^36,37 This review provides a comprehensive, mechanism-level analysis of glabridin’s depigmenting action, spanning tyrosinase inhibition, transcriptional regulation, anti-inflammatory modulation, regulation of melanosome transfer, and autophagy-mediated melanosome degradation, while also addressing the pharmacokinetic challenges and formulation strategies relevant to its clinical translation.

Overview of the Melanogenesis Pathway

Tyrosinase Enzyme Family

Melanogenesis is initiated and catalyzed by three members of the tyrosinase enzyme family: tyrosinase, tyrosinase-related protein-1 (TYRP1), and tyrosinase-related protein-2 (TYRP2).^1–3 Tyrosinase is a type III copper-containing glycoprotein. It catalyzes two sequential reactions: the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA) and the oxidation of L-DOPA to dopaquinone.¹¹ These reactions represent the rate-limiting steps in melanin biosynthesis. Therefore, tyrosinase serves as the primary target for most conventional depigmenting agents. Dopaquinone subsequently undergoes either spontaneous cyclization and polymerization to form eumelanin (brown-black pigment) or reacts with cysteine or glutathione to produce pheomelanin (red-yellow pigment).¹⁰

MITF: The Master Regulator of Melanogenesis

Microphthalmia-associated transcription factor (MITF) serves as the master transcriptional regulator of melanogenesis. It controls the expression of TYR, TYRP1, and DCT.¹¹ MITF activity is regulated by multiple upstream signaling pathways. The most prominent of these is the cAMP/PKA/CREB axis.^38,39 Upon UV exposure or α-melanocyte-stimulating hormone (α-MSH) binding to the melanocortin 1 receptor (MC1R), adenylyl cyclase is activated. This activation elevates intracellular cAMP levels. Subsequently, PKA, activated by cAMP, phosphorylates the cAMP response element-binding protein (CREB). CREB then binds to CRE elements in the MITF promoter to drive transcription.⁴⁰

Beyond the canonical cAMP/PKA pathway, MITF expression is modulated by the Wnt/β-catenin and MAPK signalling cascades.⁴¹ In the Wnt/β-catenin pathway, secreted WNT glycoproteins bind Frizzled receptors, leading to GSK-3β inactivation, cytoplasmic stabilisation of β-catenin, and its subsequent nuclear translocation. Within the nucleus, β-catenin forms a transcriptional complex with LEF/TCF that potently activates MITF transcription.² The MAPK/ERK pathway exhibits dual regulatory effects. ERK-mediated phosphorylation of MITF initially enhances its transcriptional activity. Meanwhile, this modification targets MITF for ubiquitin-dependent proteasomal degradation.⁴² This regulation reflects the complexity of melanogenesis. It also highlights the potential for pharmacological intervention at multiple nodes.

Paracrine Signaling

Melanogenesis is influenced by paracrine signaling within the epidermal melanin unit. This unit comprises one melanocyte and approximately 36 neighbouring keratinocytes.¹⁸ UV radiation stimulates keratinocytes to secrete melanogenic factors, including α-MSH, endothelin-1 (ET-1), stem cell factor (SCF), and prostaglandins. Inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) can also stimulate melanogenesis via NF-κB signalling pathways.⁴³

Melanosome Transfer

Once melanin is synthesized within melanosomes, these organelles must be transferred from melanocyte dendrites to neighbouring keratinocytes.³⁴ This process involves melanosome maturation, transport along microtubules and actin filaments, and ultimate transfer to keratinocytes. Transfer occurs via exocytosis-phagocytosis, membrane fusion, and shedding of melanosome-containing vesicles.⁴⁴ The protease-activated receptor-2 (PAR-2) on keratinocytes plays an important role in melanosome uptake through phagocytosis. Inhibition of PAR-2 signalling reduces melanosome transfer and skin pigmentation.^45,46

Glabridin: Source, Structure, and General Properties

Glabridin is one of the principal bioactive constituents of Glycyrrhiza glabra root extract. The compound possesses a characteristic isoflavan skeleton with a 2,2-dimethylpyran ring fused to the A-ring. This structure confers enhanced lipophilicity compared with other flavonoids.¹⁹

Licorice root has been used in traditional medicine for millennia across Chinese, Ayurvedic, and European pharmacopeias. Practitioners have valued it primarily for its anti-inflammatory, hepatoprotective, and immunomodulatory properties.^20,47 Glabridin constitutes approximately 0.08–0.35% of the dry root weight. This proportion varies with species, geographic origin, and extraction method.¹⁹ Notably, glabridin exhibits broad biological activities beyond its depigmenting effects. These include antioxidant, anti-inflammatory, cardioprotective, neuroprotective, and antitumour properties.²⁰ This activity stems from its ability to interact with multiple molecular targets, including enzymes, transcription factors, and signaling kinases. The chemical structures of glabridin and other depigmenting agents discussed in this review are shown in Figure 1.

Figure 1.

Chemical structures of glabridin and representative depigmenting agents discussed in this review.

Inhibition of Tyrosinase Activity

Enzyme Kinetics and Inhibition Mechanism

Yokota et al characterised the tyrosinase-inhibitory activity of glabridin. It has been showed that glabridin inhibited both monophenolase and diphenolase activities of mushroom tyrosinase in a dose-dependent manner.²¹ Furthermore, Chen et al used fluorescence quenching and UV-spectroscopy to examine the binding interaction.²² Glabridin bound to tyrosinase through hydrophobic interactions and hydrogen bonding. This binding altered the enzyme tertiary structure and quenched its intrinsic fluorescence. The static quenching mechanism indicated stable complex formation between glabridin and the enzyme. In addition, Guo et al clarified this mechanism through real-time oxygen sensing. Their oxygraphic approach monitored oxygen consumption directly during the catalytic cycle. The data revealed that glabridin inhibits the activity of mushroom tyrosinase.²³

Structure-Activity Relationships

Structure-activity relationship (SAR) studies have identified structural features that contribute to glabridin’s tyrosinase-inhibitory activity. Nerya et al examined several licorice-derived flavonoids. They found that the resorcinol moiety (1,3-dihydroxybenzene pattern) on the B-ring is essential for copper chelation within the enzyme active site.⁴⁸ Besides, Kim et al compared isoflavonoids isolated from Glycyrrhiza uralensis and found that Glabridin exhibited the most potent tyrosinase inhibition among these compounds.⁴⁹

Furthermore, Jirawattanapong et al synthesised a series of glabridin derivatives to evaluate structure-activity effects. Modifications to the hydroxyl groups on the B-ring altered inhibitory potency substantially.⁵⁰ The catechol or resorcinol hydroxyl arrangement appears critical for interaction with copper ions in the active site. This observation aligns with the broader consensus that copper-chelating moieties serve as key pharmacophores for tyrosinase inhibitors.⁵¹

Transcriptional Regulation via MITF Signalling Pathways

Modulation of the CREB-MITF and CRTC1-MITF Axis

In addition to direct tyrosinase inhibition, glabridin modulates the transcriptional machinery governing melanogenesis. The cAMP/PKA/CREB-MITF axis serves as the canonical stimulatory pathway for melanogenic gene expression.^39,40 Glabridin suppresses melanin synthesis in B16F10 melanoma cells by reducing MITF protein expression. This reduction decreased transcription of downstream targets, including TYR, TYRP1, and DCT.²⁵ Glabridin also reduced cAMP levels and inhibited PKA-mediated CREB phosphorylation, which diminished CREB-driven transcriptional activation of the MITF promoter.

Besides, studies have identified the CRTC1/MITF pathway as a new target of Glycyrrhiza glabra extract.²⁴ CRTC1 serves as a potent co-activator of CREB. It enhances transcriptional activity by bridging CREB to the basal transcriptional machinery. It has been reported that glabridin inhibits nuclear translocation of CRTC1.²² This inhibition disrupts CRTC1-CREB complex formation on the MITF promoter. The disrupted complex attenuates MITF-driven melanogenic gene expression. Therefore, glabridin is likely to target both CREB phosphorylation and the recruitment of transcriptional coactivators.

These studies highlight additional potential targets within glabridin’s signaling network. The dual action of glabridin on CREB phosphorylation and CRTC1 nuclear translocation provides transcriptional suppression. This strategy targets MITF at multiple regulatory nodes.

Wnt/β-Catenin Pathway Inhibition

Recent evidence has identified the Wnt/β-catenin pathway as a distinct target of glabridin in melanocytes. Li et al demonstrated that glabridin downregulates β-catenin protein expression in MNT-1 human melanoma cells in a dose-dependent manner.⁵² This downregulation was accompanied by reduced MITF expression and melanin content. The specificity of this mechanism was confirmed using SKL2001, a Wnt/β-catenin pathway agonist. Co-treatment with SKL2001 reversed glabridin-induced suppression of β-catenin and MITF to normal levels. The Wnt/β-catenin pathway converges with the cAMP/PKA/CREB axis on MITF transcription, but acts through distinct upstream molecular logic. Together, these three transcriptional mechanisms provide broad coverage of the signaling network governing melanogenic gene expression.

Anti-Inflammatory Mechanisms

NF-κB Pathway Suppression

Chronic inflammation drives hyperpigmentation in conditions such as post-inflammatory hyperpigmentation and melasma.⁵ Inflammatory mediators including prostaglandins, leukotrienes, and ROS stimulate melanogenesis through multiple mechanisms.⁴³ Anti-inflammatory activity therefore represents an auxiliary target for depigmenting agents.

Glabridin exhibits anti-inflammatory properties through inhibition of the NF-κB signaling pathway. It has been demonstrated that glabridin inhibits iNOS expression in LPS-stimulated macrophages.²⁹ Subsequent studies showed that glabridin suppresses intercellular adhesion molecule-1 (ICAM-1) expression, which modulates the Akt, ERK, and NF-κB signalling.²⁷

Furthermore, Chang et al examined glabridin in dermatological contexts.²⁸ Glabridin attenuated atopic dermatitis progression through downregulation of the TLR4/MyD88/NF-κB signalling cascade. Notably, Shin et al synthesised glabridin derivatives and tested their anti-inflammatory activity.²⁹ These derivatives inhibited LPS-induced inflammation in macrophages via MAPK and NF-κB pathways. The findings suggest that structural modification may preserve or enhance the anti-inflammatory pharmacophore.

MAPK Signaling Inhibition

The mitogen-activated protein kinase (MAPK) family comprises ERK1/2, JNK, and p38 MAPK. These kinases regulate both inflammatory signaling and melanogenesis.⁴³ Notably, Hou et al showed that glabridin suppresses macrophage activation by lipoteichoic acid. Glabridin inhibits the MAPKs-IL-1β-iNOS axis in both peritoneal and alveolar macrophages.³⁰ Shan et al extended these findings to neuroinflammation.³¹ Glabridin reduces neuroinflammation through MAPK-dependent mechanisms.³²

These anti-inflammatory effects carry direct implications for melanogenesis regulation. NF-κB and MAPK activation and downstream cytokine production can stimulate melanocyte activity through paracrine mechanisms. Taken together, glabridin is highly likely to attenuate inflammation-driven melanogenesis by suppressing these signals.

Inhibition of Melanosome Transfer

Even when melanin synthesis is inhibited, the transfer of melanosomes from melanocytes to keratinocytes represents an independent and important determinant of skin pigmentation.³⁴ The PAR-2, expressed on keratinocytes but not melanocytes, plays a pivotal role in regulating melanosome phagocytosis by keratinocytes.^46,53

Studies have indicated that PAR-2 activation promotes melanosome uptake by keratinocytes and that inhibition of this pathway results in visible skin lightening.⁴⁶ The mechanism involves PAR-2-mediated activation of Rho GTPases, which regulate cytoskeletal reorganization necessary for phagocytic uptake of melanosomes.⁴⁶ Moreiras et al subsequently refined this model, showing that melanocore uptake by keratinocytes occurs specifically through phagocytosis and involves PAR-2 internalization.⁴⁴

Emerging evidence has reported that glabridin inhibits melanin transfer.⁵² Using a UVB-irradiated MNT-1/HaCaT co-culture system, Li et al demonstrated that 5 mM glabridin reduces melanin transfer to keratinocytes by 66.5%, as quantified by immunofluorescence co-staining of the melanosomal marker TRP-1 and the keratinocyte marker pan-cytokeratin. This reduction exceeds that achieved by 200 mM niacinamide (33.5%), a well-established melanosome transfer inhibitor. Mechanistically, Li et al linked glabridin’s anti-transfer effect to the regulation of Rho family GTPases. This Rho-GTPase-dependent mechanism represents a distinct route through which glabridin influences melanin transfer, independent of its effects on melanin synthesis.

Autophagy-Mediated Melanosome Degradation

Once melanosomes have been transferred to keratinocytes, their fate within the recipient cell represents an important determinant of skin colour. Several studies have demonstrated that activation of autophagy in keratinocytes accelerates melanosome degradation and that pharmacological inhibition of autophagy results in melanosome accumulation and darkening of the skin.^54,55 These findings established autophagy as a biologically significant mechanism for regulating pigmentation.

Emerging evidence has reported that glabridin activates autophagy-mediated melanosome degradation in keratinocytes. Treatment with glabridin increases the expression of autophagy-related proteins and promotes the formation of autophagosomes that colocalize with melanosomes.³⁵ This mechanism represents a post-transfer clearance pathway that is mechanistically distinct from the compound’s effects on melanocyte biology, expanding its known pharmacological profile.

Pharmacokinetics and Formulation Strategies

Bioavailability Challenges

Despite its multi-target pharmacological profile, glabridin faces significant pharmacokinetic challenges that limit its clinical application. Simmler et al reviewed the phytochemistry and biological properties of glabridin, highlighting its poor aqueous solubility, photosensitivity, and susceptibility to oxidative degradation as major barriers to formulation and delivery.¹⁹ The compound’s high lipophilicity facilitates membrane permeation, yet it also leads to poor dissolution in aqueous biological fluids. This results in limited oral bioavailability and inconsistent topical absorption.

Novel Delivery Systems

To overcome these pharmacokinetic limitations, researchers have developed numerous delivery strategies for glabridin. These approaches fall into several categories: 1) Particle-size reduction strategies, including nanosuspensions⁵⁶ and smartPearls amorphous silica particles,⁵⁷ improve dissolution rate and dermal deposition. 2) Inclusion complexation with cyclodextrins enhances aqueous solubility while preserving biological activity.⁵⁸ 3) Lipid-based carriers such as liposomes offer cell-specific targeting, as exemplified by the MC1R-targeted formulation developed by Cheng et al⁵⁹ 4) Microneedle-based transdermal systems bypass the stratum corneum barrier.⁶⁰ 5) Nucleic acid frameworks, such as tetrahedral framework nucleic acid loaded with glabridin, provide programmable delivery.⁶¹ Each strategy offers distinct advantages in penetration depth, stability, targeted delivery, and scalability. These delivery innovations reflect substantial scientific investment in overcoming glabridin’s pharmacokinetic limitations. These findings suggest that formulation technology may be the key enabler for translating glabridin’s multi-target activity into clinical efficacy.

Clinical Evidence

Clinical studies evaluating glabridin’s depigmenting efficacy provide encouraging evidence supporting its therapeutic potential. Cantelli et al conducted a 6-month open-label pilot study evaluating a proprietary gel containing glabridin, andrographolide, and apolactoferrin in adult women with epidermal melasma.⁶² The study demonstrated improvement in melasma appearance, assessed by dermatological scoring systems and colorimetric measurements. In addition, Zhang et al evaluated formulations combining 4-n-butylresorcinol, licochalcone A, and glabridin at optimized ratios. These formulations produced enhanced lightening effects through synergistic tyrosinase inhibition.⁶³ However, the multi-component formulation makes it difficult to attribute the observed effects solely to glabridin.

Systematic reviews have provided context for evaluating natural depigmenting agents. Wang et al conducted a systematic review and meta-analysis of topical botanical products for melasma, concluding that natural agents including licorice derivatives demonstrate moderate efficacy with favourable safety profiles.⁶⁴ In addition, Hollinger et al reviewed the evidence for natural ingredients in hyperpigmentation management, identifying licorice extract/glabridin among the agents with the strongest supporting evidence.⁶⁵ Similarly, Fisk et al concluded that licorice-derived compounds represent one of the most promising botanical approaches for treating hyperpigmentation.⁶⁶

Notably, all existing clinical studies are limited by small sample sizes, short follow-up durations, and the use of multi-component formulations that preclude attribution of efficacy to glabridin alone. Large-scale, randomised controlled trials comparing glabridin monotherapy against established agents such as hydroquinone are needed.

Comparative Analysis with Other Depigmenting Agents

A comparison of glabridin with established depigmenting agents clarifies its multi-target profile. Conventional depigmenting agents can be categorised by their primary mechanism of action: tyrosinase inhibitors (hydroquinone, kojic acid,¹⁴ arbutin¹⁵), melanosome transfer inhibitors (niacinamide⁶⁷), melanin degradation promoters (ascorbic acid¹⁶), and anti-inflammatory agents (corticosteroids).⁶⁸

Niacinamide is well-characterised for its ability to inhibit melanosome transfer without directly affecting tyrosinase activity.⁶⁷ Hakozaki et al demonstrated that niacinamide reduces cutaneous pigmentation by suppressing melanosome transfer from melanocytes to keratinocytes. In contrast, glabridin acts on both melanin synthesis and potentially melanosome transfer. This provides a broader mechanism of action.

The multi-target profile of glabridin also distinguishes it from kojic acid and arbutin, which function primarily as tyrosinase inhibitors with limited effects on other melanogenesis-regulating pathways.¹⁴ While hydroquinone remains an effective single-agent depigmenting compound, its adverse effect profile and regulatory restrictions favour the development of safer multi-target alternatives. Parvez et al provided a comprehensive survey of depigmenting mechanisms, highlighting the need for agents that combine efficacy with safety.¹³ Glabridin appears well-positioned to meet this need. Together, these studies contextualize glabridin’s position among botanical depigmenting agents.

Discussion

This review has systematically evaluated the multi-target depigmenting mechanisms of glabridin. Glabridin modulates melanogenesis through five complementary pathways: tyrosinase inhibition, transcriptional regulation via MITF signalling, anti-inflammatory activity, inhibition of melanosome transfer, and promotion of melanosome degradation. This breadth of action distinguishes glabridin from conventional single-target agents such as hydroquinone and kojic acid, which rely primarily on tyrosinase inhibition and carry well-documented safety liabilities.

Importantly, the strength of evidence varies considerably across the proposed mechanisms. Tyrosinase inhibition is supported by multiple independent studies employing complementary experimental approaches, including enzyme kinetics, fluorescence spectroscopy, molecular docking, and real-time oxygen sensing. MITF-mediated transcriptional regulation and anti-inflammatory effects are also supported by a growing body of evidence across multiple research groups. These three can therefore be considered well-established mechanisms. In contrast, the regulation of melanosome transfer and autophagy-mediated melanosome degradation are each currently supported by a single study, and should be regarded as emerging evidence that requires independent validation. Future studies employing diverse experimental models are needed to confirm these findings and establish their reproducibility.

Despite this promising preclinical profile, several limitations must be acknowledged. The majority of mechanistic studies have employed in vitro models, predominantly B16F10 murine melanoma cells and MNT-1 human melanoma cells. These models offer experimental tractability but may not fully recapitulate the behaviour of primary human melanocytes in situ. Furthermore, the concentration ranges used in many in vitro studies exceed the likely free-drug concentrations achievable in human epidermis after topical application. The clinical evidence base remains sparse, comprising small pilot studies and open-label trials with multi-component formulations that preclude attribution of efficacy specifically to glabridin.

Pharmacokinetic constraints present additional hurdles. Glabridin’s poor aqueous solubility, low oral bioavailability, and photosensitivity limit its therapeutic utility in unformulated preparations. However, advances in nanotechnology, cyclodextrin complexation, and receptor-targeted liposomes offer credible pathways to improved delivery. Dissolving microneedle systems may be especially relevant for transdermal administration, as they bypass the stratum corneum barrier and deposit glabridin directly within the epidermis.

From a translational perspective, glabridin’s multi-target mechanism and favourable safety profile make it well-suited for incorporation into both cosmetic and dermatological formulations. In cosmetic applications, the growing consumer demand for natural and safe skin-lightening ingredients creates a favourable market environment for botanical alternatives to hydroquinone. In dermatological applications, glabridin may serve as a complementary agent in the management of melasma and post-inflammatory hyperpigmentation, particularly for patients who cannot tolerate conventional depigmenting therapies. Consistent with this potential, active investment in glabridin-based formulation development, including targeted delivery systems such as MC1R-directed liposomes,⁵⁹ reflects the growing translational interest in this compound. However, successful translation from preclinical evidence to commercial and clinical application will depend on overcoming its pharmacokinetic limitations through continued advances in formulation technology, as well as large-scale randomised controlled trials to establish efficacy and safety in human populations.

Several key research priorities should be addressed in future studies. First, well-designed, large-scale randomized controlled trials comparing glabridin monotherapy against established agents such as hydroquinone are needed to establish its clinical efficacy and safety. Second, human pharmacokinetic studies are required to determine the actual skin penetration, bioavailability, and effective concentrations achievable in the epidermis following topical application. Third, long-term safety studies are warranted to fully characterize the safety profile of glabridin.

In summary, glabridin exemplifies the potential of natural multi-target agents in depigmentation therapy. By concurrently modulating multiple melanogenesis-regulatory pathways while maintaining a favourable safety profile, glabridin stands as a promising therapeutic candidate for skin pigmentation. Realising this therapeutic potential will hinge on continued formulation innovation and rigorous clinical validation.

Funding Statement

This research received no external funding.

Data Sharing Statement

No new data were generated or analysed in this review article.

Ethical Approval

No ethical approval was required as this is a review article with no original research data.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflict of interest.