Progress in the Application of Exosomes in Androgenetic Alopecia: Focusing on Molecular Mechanisms

Abstract

Androgenetic alopecia (AGA) is the most common type of hair loss worldwide, characterized by progressive miniaturization of hair follicles and a shortened anagen phase. Currently, FDA-approved drugs for AGA treatment, minoxidil and finasteride, cannot provide satisfactory outcomes for all patients and can sometimes cause side effects. Therefore, there has been an urgent need for novel and safer therapeutic strategies. At the cellular and molecular level, the pathogenesis of AGA is closely associated with the dysregulation of signaling pathways in hair follicles. As nano-sized extracellular vesicles secreted by cells, exosomes carry bioactive substances such as proteins, lipids, and nucleic acids, thereby playing a crucial role in intercellular and intracellular communication. By modulating dysregulated signaling pathways in hair follicles, exosome therapy offers a highly promising therapeutic option for AGA patients. However, it should be noted that current evidence remains limited, and more well-designed studies are required to validate the long-term efficacy and safety of exosome-based therapies for AGA. Also, addressing challenges in the production, application, and regulation of exosomes is indispensable for promoting the future clinical application of exosome-based therapies in AGA treatment. This review summarizes the preclinical and clinical progress in exosome-based therapies for AGA treatment, with a particular focus on their molecular mechanisms, especially their regulation of key signaling pathways involved in AGA pathogenesis, such as Wnt/β-catenin, Shh, TGF-β/Smad, PI3K/AKT, and MAPK signaling pathways. These endeavors are expected to provide researchers with valuable scientific insights and practical information for AGA drug discovery.

Introduction

Overview of Androgenetic Alopecia

Androgenetic alopecia (AGA), the most common type of hair loss globally, is characterized by progressive miniaturization of hair follicles (HF) accompanied by a shortened anagen phase and a prolonged telogen phase during the hair cycle. This process ultimately leads to reduced hair shaft diameter, leading to progressive hair thinning and eventual follicular dropout.¹ The exact pathogenesis of AGA has not been fully elucidated. So far, genetic predisposition, androgen metabolism, local inflammatory responses, perifollicular fibrosis, and disrupted energy metabolism of hair follicles are considered major pathogenic mechanisms of AGA.² At the cellular and molecular level, the pathogenetic process of AGA has been shown to be closely related to certain hair follicle signaling pathways.³ Clinically, AGA can be divided into two types: male pattern hair loss (MPHL) and female pattern hair loss (FPHL). MPHL is characterized by hairline recession starting from the frontal and temporal scalp and extending to the vertex, whereas FPHL typically begins with hair thinning around the vertex scalp and often with the anterior hairline remaining intact.⁴

As a prevalent condition affecting hundreds of millions of people worldwide, AGA is increasingly characterized by earlier onset and imposes a heavy burden on patients’ appearance, self-esteem, and psychological well-being. Therefore, there has been an increasing clinical need for effective treatment.⁵ However, therapeutic options for AGA patients remain limited. Currently, only minoxidil and finasteride have been approved by the Food and Drug Administration (FDA) for AGA treatment, and both exhibit limitations.⁶ The efficacy of minoxidil largely depends on sulfotransferase activity, which varies among individuals.⁷ Notably, patients may confront initial shedding, contact dermatitis, and undesirable hair growth in non-treatment areas during the use of minoxidil.^8–10 Additionally, though several mechanisms have been proposed, including the activation of potassium ion channels, the precise mechanism of action in AGA remains uncertain.⁷ The other approved drug for AGA, finasteride, works by inhibiting 5α-reductase and blocking the conversion of testosterone to dihydrotestosterone (DHT). However, its clinical application is restricted by potential adverse effects, particularly sexual dysfunction, which may persist even after drug discontinuation.¹¹ Additionally, concerns regarding teratogenicity and possible associations with depressive symptoms further limit its use.^12,13 Therefore, there has been a lack of safer and more effective therapeutic options with well-defined mechanisms during the past few decades.

Based on current understanding of AGA pathogenesis, dysregulation of key signaling pathways plays a central role in hair cycling and follicle regeneration. Advances in molecular biology have further shifted the focus of AGA treatment towards these pathways, with particular emphasis on Wnt/β-catenin, Sonic Hedgehog (Shh), Transforming Growth Factor-β(TGF-β)/Smad, Phosphatidylinositol 3-kinase(PI3K)/AKT, and Mitogen-Activated Protein Kinase (MAPK) signaling pathways.³ Given their central roles in hair follicle biology, these pathways have emerged as important therapeutic targets. In this context, exosome-based therapies, which can modulate multiple signaling pathways simultaneously, have attracted growing attention, offering new opportunities for AGA treatment.

Overview of Exosomes

Exosomes are a class of extracellular vesicles with a diameter of 30–150 nm, which are secreted by nearly all cell types in physiological and pathological conditions.^14,15 They were first identified in 1983 during the maturation of reticulocytes into erythrocytes and were once considered cellular debris without biological functions.¹⁶ However, it has been revealed that exosomes play critical roles in intercellular communication over the past years. Exosome biogenesis begins with the inward budding of the plasma membrane, forming early endosomes that subsequently mature into late endosomes. Further inward budding of the endosomal membrane gives rise to intraluminal vesicles (ILVS), leading to the formation of multivesicular bodies (MVBs). Upon fusion of MVBs with the plasma membrane, these vesicles are released into the extracellular space as exosomes.^14,15,17 During the process, exosomes are enriched on their surface with transmembrane proteins, receptors, and other functional molecules. Meanwhile, their cargoes include various bioactive substances such as proteins, lipids, RNA, and even DNA, which vary widely depending on their source cells.¹⁸ Once delivered to recipient cells, signals are transferred through receptor-ligand interactions, direct membrane fusion, or endocytosis. Therefore, exosomes function as key mediators of both local and long-distance intercellular communication.¹⁵

Owing to their nanoscale size, lipid bilayer stability, and capacity for bioactive cargo delivery, exosomes have attracted interest as acellular therapeutic agents, particularly in dermatology.¹⁹ Compared with synthetic nanoparticles, exosomes exhibit several advantages: intrinsic ability to carry bioactive substances such as RNA, DNA and proteins; natural targeting properties derived from their source cells; fulfilling stability in body fluids due to their double-layered membrane and nanoscale size; immune tolerance when using autologous-derived exosomes; and inherent ability to overcome biological barriers such as the blood-brain barrier (BBB).^20–28

These unique properties make exosomes promising candidates for therapeutic applications. As they transfer information critical for skin homeostasis and disease pathogenesis, their role in treating AGA is being explored.²⁹ Multiple studies have demonstrated that exosomes contain growth factors, cytokines, and microRNAs that can modulate signaling pathways involved in hair cycling and follicle regeneration. By modulating these signaling pathways, exosomes can counteract androgen-induced pathological processes and promote follicle regeneration in AGA. Accordingly, exosome therapy has emerged as a promising strategy for AGA treatment.

Although exosomes hold immense therapeutic potential, their clinical translation is facing several limitations that remain to be solved. From a manufacturing perspective, exosome therapy faces challenges of low yields and purity, high costs, batch-to-batch variability, and overly complicated isolation methods.³⁰ From a clinical perspective, there is a lack of standardized administration protocols and sufficient supporting data, and more clinical evidence is expected to validate dosing regimens and support the efficacy and safety of exosome therapy for clinical application.³¹ From a regulatory perspective, variations in production processes, product definitions, and quality control metrics have resulted in a lack of unified regulatory standards, further complicating the pathway to clinical adoption and regulatory approval.³² Collectively, standardized protocols, robust clinical trials, and globally harmonized regulatory frameworks will be essential to ensure safety, efficacy, and reproducibility. Addressing these multifaceted challenges is indispensable for advancing exosome-based therapies toward routine clinical use.

This review summarizes recent preclinical and clinical advances in the application of exosomes for AGA treatment, with particular emphasis on their possible molecular mechanisms, especially their roles in modulating key signaling pathways involved in AGA pathogenesis, such as Wnt/β-catenin, Shh, TGF-β/Smad, PI3K/AKT, and MAPK signaling pathways (Figure 1). These insights are expected to provide valuable guidance for future therapeutic development and drug discovery in AGA.

Figure 1.

Possible Molecular Mechanisms of Exosome-based Therapies for Androgenetic Alopecia. Exosomes carry various bioactive molecules and regulate multiple signaling pathways involved in hair biology. Black upward arrows indicate activation or upregulation, while red arrow-shaped symbols indicate inhibition or downregulation.

Possible Molecular Mechanisms of Exosome-Based Therapies for Androgenetic Alopecia

Wnt/β-Catenin Signaling Pathway

Introduction of the Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling pathway, also known as the canonical Wnt pathway, consists of key components such as Wnt ligands, β-catenin, and Frizzled (Fzd) receptors. Activation of this pathway is essential for both physiological hair cycling and follicle regeneration after injury.³³ When Wnt ligands bind to Frizzled receptors and LRP5/6 co-receptors, they inhibit the β-catenin destruction complex composed of adenomatosis polyposis coli (APC), Axin, and glycogen synthase kinase-3 beta (GSK-3β), further preventing the phosphorylation and degradation of β-catenin. Stable β-catenin then accumulates in the cytoplasm, available for translocation into the nucleus, where it partners with TCF/LEF transcription factors to activate downstream genes such as Cyclin D1 and LEF1, ultimately promoting entry of hair follicles into the anagen phase.³⁴

As a pivotal regulator of hair cycling and follicle regeneration, the Wnt/β-catenin signaling pathway contributes to orchestrating the telogen-to-anagen transition, activation of hair follicle stem cells (HFSC), and tissue repair. Moreover, it maintains the ecological niche of HFSC and regulates the function of dermal papilla cells (DPC), both of which are crucial for initiating hair cycling and follicle regeneration.³³ Therefore, this pathway is considered a central target for promoting hair growth and follicle regeneration.

Wnt/β-Catenin Signaling Pathway in AGA Pathogenesis

The crosstalk between androgens and the Wnt/β-catenin signaling pathway is considered to play a central role in the pathogenesis of AGA. Early evidence first established this link by demonstrating that DHT inhibits Wnt3a-dependent keratinocyte proliferation and Wnt signal-mediated transcription. Notably, DPCs derived from AGA patients exhibit elevated expression of androgen receptor (AR) and enhanced nuclear interaction with β-catenin, suggesting that DHT interferes with Wnt signaling at the level of intracellular signal transduction.³⁵ Mechanistic insights have subsequently revealed that androgen-mediated inhibition of Wnt signaling is likely driven by the DHT-prostaglandin D2 (PGD2) -CXXC5 axis. Specifically, DHT upregulates prostaglandin D2 synthase (PTGDS), leading to increased PGD2 production, which induces CXXC5, a negative regulator of the Wnt/β-catenin signaling pathway.³⁶ Androgen exposure has also been shown to enhance GSK-3β activity in DPCs, leading to phosphorylation and inactivation of β-catenin, thereby inhibiting Wnt signaling and impairing HFSC differentiation.³⁷ Collectively, these findings indicate that androgen signaling suppresses Wnt/β-catenin activity through multiple intracellular mechanisms, thereby contributing to impaired HFSC differentiation and follicle miniaturization.

Through the inhibition of Wnt signaling, androgens have been proven to deregulate DPC-secreted factors involved in normal HFSC differentiation, potentially contributing to AGA. Leirós et al demonstrated that the action of androgens impairs DPC’s ability to induce HFSC differentiation, and activation of the Wnt/β-catenin signaling pathway restores its differentiating ability.³⁷ The group later identified DKK1 and Wnt10b as key androgen-regulated paracrine factors that modulate the inhibition of HFSC differentiation involved in AGA, and the imbalance of Wnt agonists and antagonists may contribute to the development of AGA.³⁸

Consistent with these observations, transcriptomic analyses further validate the important role of Wnt signaling in AGA. Notably, DKK-1, as a potent inhibitor of the Wnt/β-catenin signaling pathway, has been identified as one of the most significantly upregulated genes in balding DPCs, and its neutralization has been shown to reverse growth inhibition of outer root sheath cells induced by DHT.³⁹ These findings further reinforce the role of DKK-1 as a key mediator of androgen-induced Wnt suppression. Also, Wnt signaling pathway-related genes, SERPINF1 and SFRP2, are validated to be upregulated in AGA HFs and may play important roles in AGA.⁴⁰

Collectively, these findings indicate that the Wnt/β-catenin signaling pathway may be potentially utilized as a therapeutic target for AGA.

Exosome Therapy That Regulates the Wnt/β-Catenin Signaling Pathway

Given that suppression of the Wnt/β-catenin signaling pathway is a key mechanism underlying AGA pathogenesis, activation of Wnt signaling has emerged as a promising therapeutic strategy. In this context, exosomes, as important mediators of intercellular communication, have attracted increasing attention due to their ability to activate the Wnt/β-catenin signaling pathway and contribute to hair growth and follicle regeneration.

Accumulating evidence indicates that exosomes derived from various cell types can promote hair growth primarily through activation of the Wnt/β-catenin signaling pathway. Mechanistically, this effect is mediated through multiple complementary processes. One mechanism involves microRNAs carried by exosomes that relieve inhibitory constraints on Wnt signaling by targeting Wnt antagonists. For example, Hu et al demonstrated that miR-218-5p was notably upregulated in dermal papilla spheroid-derived exosomes and promoted hair growth by downregulating Wnt signaling inhibitor SFRP2 and upregulating β-catenin.⁴¹ In addition, exosomes can stabilize β-catenin by modulating key regulatory proteins. In particular, inhibition of GSK-3β, a critical negative regulator of β-catenin, prevents its degradation and sustains pathway activation.⁴² Furthermore, exosomes can activate downstream components of the Wnt signaling cascade. Yu A et al validated that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-Exos) enrich miR-21-5p and let-7b-5p, which target key genes such as Cyclin D1, c-MET, and LEF1 to activate the Wnt/β-catenin pathway, thus promoting hair shaft regrowth in AGA models.⁴³ Importantly, these mechanisms may collectively contribute to counteracting androgen-induced inhibition in AGA by restoring Wnt/β-catenin signaling activity.

Consistent with these molecular findings, functional studies further support the pro-regenerative effects of exosomes on hair follicles. Adipose-derived stem cell exosomes (ADSC-Exos) have been shown to promote proliferation and migration of DPCs while reducing H₂O₂-induced apoptosis in vitro. In vivo, ADSC-Exos-treated models exhibit improved hair growth, increased hair follicle number, and thickened dermis.⁴⁴ Similarly, platelet-rich plasma-derived exosomes (PRP-Exos) also stimulate DPC proliferation and enhance follicle regeneration through the activation of the Wnt/β-catenin signaling pathway.⁴⁵ Of note, while these in vivo studies utilized standard mouse models with untreated or minoxidil-treated controls, they did not employ androgen-induced AGA models. Therefore, although these findings support the pro-regenerative potential of exosomes, their specific efficacy in counteracting androgen-mediated follicle regression warrants further investigation in appropriate AGA models. In this regard, recent evidence from AGA models has provided more direct support. Human amniotic mesenchymal stem cell-derived exosomes (hAMSC-Exos) have been shown to accelerate hair growth in AGA mice and alleviate DHT-induced DPC damage through activation of the Wnt/β-catenin signaling pathway.

Collectively, these findings suggest that exosomes promote follicle regeneration by restoring Wnt/β-catenin signaling through multiple mechanisms, including relieving pathway inhibition, activating downstream signaling components, and reversing androgen-mediated suppression. This multi-level regulatory capacity highlights the therapeutic potential of exosome-based strategies for the treatment of AGA. Nevertheless, considering the limited direct evidence from AGA-specific models, future investigations employing androgen-induced AGA models are warranted to validate the efficacy of exosome-based Wnt/β-catenin activation in counteracting follicular miniaturization. Additionally, more comparative studies evaluating exosome therapy against standard AGA treatments in these models would strengthen its therapeutic potential and facilitate clinical translation.

Shh Signaling Pathway

Introduction of the Shh Signaling Pathway

The Shh signaling pathway plays a crucial role in regulating hair follicle morphogenesis, cycling, and regeneration. Shh ligands secreted within the hair follicle microenvironment initiate signaling by binding to the Patched (Ptc) receptor, thereby relieving its inhibitory effect on Smoothened (Smo). The activation leads to nuclear translocation of Gli transcription factors, which regulate target gene expression and promote the proliferation of hair matrix cells, ultimately driving hair follicle growth and initiation of the hair cycle.⁴⁶

Shh Signaling Pathway in AGA Pathogenesis

Shh signaling is closely associated with the Wnt/β-catenin pathway and functions as its downstream mediator. The pathway is critical for both hair follicle morphogenesis during embryogenesis and hair growth in individuals.⁴⁷ During embryogenesis, Shh signaling is essential for controlling ingrowth and morphogenesis, as evidenced by arrested follicle development in the Shh mutant embryo.⁴⁸ Subsequently, in postnatal skin, Shh signaling serves as a key regulator of hair growth and follicle cycling by inducing telogen-to-anagen transition.⁴⁹ Given that Wnt/β-catenin signaling is suppressed in AGA, the activity of its downstream effector, Shh signaling, may also be impaired, leading to reduced hair follicle proliferation and defective cycling. Furthermore, emerging evidence has directly implicated the Shh pathway dysregulation in AGA pathogenesis. Fu et al demonstrated that the AGA-associated miR-22-3p directly targets CLIC4 and suppresses Shh pathway activation, as evidenced by reduced Gli1 and Gli2 transcriptional activity, thereby impairing HFSC proliferation and contributing to follicular miniaturization. Therefore, restoration of Shh signaling may also represent a potential therapeutic strategy for AGA.

Exosome Therapy That Regulates the Shh Signaling Pathway

So far, there is limited direct evidence demonstrating that exosomes can treat AGA by selective activation of the Shh signaling pathway. However, emerging studies suggest that exosomes may modulate Shh signaling in conjunction with other pathways and contribute to hair growth. For instance, Zhou et al reported that DPC-Exos promoted hair growth in mice by activating both the Wnt/β-catenin and Shh signaling pathways.⁵⁰ This finding is particularly relevant given that Shh signaling is required for β-catenin-induced de novo hair follicle formation.⁵¹ Although direct mechanistic evidence remains limited, these observations suggest that exosome-mediated activation of the Shh signaling pathway, particularly in coordination with Wnt signaling, may represent a promising therapeutic avenue for AGA.

TGF-β/Smad Signaling Pathway

Introduction of the TGF-β/Smad Signaling Pathway

The TGF-β/Smad signaling pathway plays an important role in regulating hair follicle formation and development, primarily exerting inhibitory effects on cell proliferation and promoting apoptosis.^52,53 TGF-β is a family of multifunctional cytokines belonging to the TGF-β superfamily, and the signal transduction downstream of the TGF-β receptors involves the Smad family.^54,55 Mammals have three classes of Smads: the receptor-regulated Smad (R-Smad), the co-mediator Smad (Co-Smad), and the inhibitory Smad (I-Smad). TGF-β ligands initiate signaling by binding to TGF-β receptors type I and type II. The type II receptor phosphorylates the type I receptor, leading to phosphorylation of R-Smads (Smad2, Smad3). Then phosphorylated R-Smad is translocated into the nucleus, where it complexes with Co-Smad (Smad4) to regulate target gene expression.⁵⁶ While I-Smads, Smad6 and Smad7, inhibit the phosphorylation of R-Smads, thus negatively modulating this pathway.⁵⁷

TGF-β/Smad Signaling Pathway in AGA Pathogenesis

Activation of the TGF-β/Smad signaling pathway is a key event in AGA pathogenesis and takes part in androgen-induced hair follicle regression. Elevated expression of TGF-β1 and TGF-β2 has been observed in hair follicles of AGA patients, where they act as essential inducers of follicle miniaturization.^{54,56,58–60}

TGF-β1 plays a central role in inhibiting cell proliferation and inducing apoptosis.^58–60 Androgen stimulation has been shown to increase the secretion of both total and active TGF-β1 in the cocultured DPCs, while neutralizing TGF-β1 antibody reverses the androgen-induced growth inhibition of keratinocytes.⁶⁰ TGF-β1 has also been proven to induce the apoptosis of endothelial cells, thus contributing to AGA development.⁶¹ Furthermore, TGF-β1 contributes to the development of perifollicular fibrosis and enhances AR transactivation, further exacerbating follicle miniaturization and promoting the development of AGA.^62,63

TGF-β2 also acts as a critical downstream mediator of androgen signaling.^54,56 The proposed “catagen cascade” describes the following sequence of reactions expected to occur in AGA: testosterone delivered to hair follicles is converted to DHT by type II 5α-reductase; DHT then stimulates the synthesis of TGF-β2 in DPCs; TGF-β2 activates caspase-dependent apoptosis in hair matrix cells, ultimately leading to premature follicle regression.⁵⁶

Collectively, TGF-β1 and TGF-β2 synergistically promote follicle miniaturization by inducing apoptosis, inhibiting proliferation, and accelerating the transition to the catagen phase.

Exosome Therapy That Regulates the TGF-β/Smad Signaling Pathway

Recent studies have demonstrated that exosome-based therapies can counteract AGA progression by suppressing the TGF-β/Smad signaling pathway. Liang et al validated that ADSC-Exos are enriched in miR-122-5p, which inhibits the TGF-β/Smad signaling pathway by targeting Smad3. Functionally, this regulatory effect is manifested across multiple levels. At the cellular level, ADSC-Exos promote the proliferation, migration, and differentiation of DPCs and upregulate key hair growth-related factors such as cyclins, β-catenin, versican, and BMP2. At the organ level, they promote the proliferation of ex vivo HFs and induce the transition to the anagen phase. In vivo studies further confirm that ADSC-Exos significantly promote hair growth in AGA mice models.⁶⁴ Consistently, another study has shown that ADSC-Exos are also enriched in miR-574-3p and miR-125a-5p, which inhibit the TGF-β1/Smad signaling pathway by targeting Smad2, alleviating DHT-induced impairment of DPCs, and promoting hair growth.⁶⁵

These findings highlight that exosomes promote hair regeneration not by activating proliferative pathways alone, but also by relieving inhibitory signaling. Collectively, these findings indicate that exosome-mediated delivery of regulatory microRNAs can effectively attenuate TGF-β/Smad signaling at multiple nodes, thereby restoring hair follicle activity and promoting hair growth in AGA.

PI3K/AKT Signaling Pathway

Introduction of the PI3K/AKT Signaling Pathway

The PI3K/AKT signaling pathway is integral to the regulation of a spectrum of cellular functions, encompassing cell survival, metabolism, and growth. Upon activation by growth factors such as insulin-like growth factors (IGFs), epidermal growth factors (EGFs), and fibroblast growth factors (FGFs), AKT phosphorylates multiple downstream targets that govern critical processes such as progression of the cell cycle, inhibition of apoptosis, and modulation of cellular metabolism.³³ In the context of hair biology, AKT signaling plays a particularly prominent role in the activation and maintenance of HFSCs and facilitates the transition from telogen to anagen.^66,67 Furthermore, AKT signaling is involved in regulating the functions of DPCs by enhancing their proliferative capacity and facilitating their interaction with HFSCs, and this interaction is essential for establishing and maintaining the hair cycle.³³

PI3K/AKT Signaling Pathway in AGA Pathogenesis

Dysregulation of the PI3K/AKT signaling pathway is implicated in the pathogenesis of AGA.^68,69 Transcriptomic analyses of miniaturized follicles from AGA patients have revealed significant downregulation of PI3K/AKT-related genes compared with normal follicles.⁶⁸ Given the central role of AKT signaling in promoting cell proliferation and stem cell activation, its suppression may contribute to impaired hair follicle regeneration, reduced cellular proliferation, and follicle miniaturization observed in AGA.

Exosome Therapy That Regulates the PI3K/AKT Signaling Pathway

Although there is limited direct evidence demonstrating that exosomes treat AGA specifically by modulating the PI3K/AKT signaling pathway, emerging studies suggest that exosomes can promote hair regeneration by activating this pathway. Chen et al verified that hUCMSC-Exos significantly enhance the proliferation of DPCs through modulating the PI3K/AKT signaling pathway by activating AKT signaling, hUCMSC-Exos significantly upregulate the expression of cell cycle-related proteins Cyclin D1 and β-catenin, and increase cell populations in the S and G2/M phases, thereby effectively promoting cell proliferation and hair regeneration.⁷⁰ Although these findings are not specific to AGA models, they provide mechanistic evidence that exosome-mediated activation of AKT signaling can enhance hair follicle cell activity. Given that this pathway is downregulated in AGA, reactivation of AKT signaling through exosome-based delivery may represent a promising therapeutic strategy.

MAPK Signaling Pathway

Introduction of the MAPK Signaling Pathway

The MAPK signaling pathway represents a critical regulator of cell proliferation and differentiation, playing an essential role in hair follicle morphogenesis and regeneration. Activated by diverse extracellular signals, including growth factors, cytokines, and hormones, MAPK signaling facilitates the activation of transcription factors that modulate gene expression patterns essential for hair growth and follicle regeneration.³³

MAPK Signaling Pathway in AGA Pathogenesis

Dysregulation of the MAPK signaling pathway contributes to the pathogenesis of AGA. IGF-1, a key activator of the MAPK pathway, is significantly downregulated in AGA.^71,72 Research has found that in AGA patients, AR directly promotes the transcription of miR-221, which inhibits IGF-1 expression. This downregulation of IGF-1 leads to the inactivation of the MAPK pathway in DPCs and the PI3K/AKT pathway in dermal sheath cells, resulting in reduced cellular proliferation and impaired hair growth.⁶⁹ These findings highlight that inhibition of MAPK signaling is a key event linking androgen signaling to follicle miniaturization in AGA.

Exosome Therapy That Regulates the MAPK Signaling Pathway

Emerging evidence suggests that exosome-based therapies may promote hair regeneration by reactivating the MAPK signaling pathway. Mao et al demonstrated that hUCMSC-Exos significantly improve hair growth in AGA mice, as evidenced by increased hair length, diameter, and follicle number at the mechanistic level, hUCMSC-Exos enhance follicle regeneration by promoting HFSC stemness and proliferation, as indicated by upregulation of stemness-related proteins (K15 and CD200) and the proliferation marker (PCNA). Transcriptome sequencing analysis further reveals that the genes upregulated following exosome treatment are mainly enriched in the MAPK signaling pathway. Collectively, the results suggest that exosome-mediated activation of MAPK signaling restores proliferative capacity and stem cell activity within hair follicles, thereby contributing to hair regeneration in AGA.⁷³

Other Signaling Pathways

Bone Morphogenetic Proteins (BMP) Signaling Pathway

BMPs, members of the TGF-β superfamily, regulate hair follicle biology through Smad-dependent signaling. Upon ligand binding, BMP receptors activate intracellular Smad cascades, leading to transcriptional regulation of genes involved in cell growth, differentiation, and apoptosis.^74,75 Through the process, BMP signaling plays a crucial role in maintaining homeostasis. On one hand, BMP signaling is essential for maintaining DPC’s inductive capacity and promoting HFSC differentiation toward the hair lineage.^76,77 On the other hand, it maintains HFSC quiescence and suppresses premature anagen initiation.^78,79

Dysregulation of BMP signaling has been implicated in the pathogenesis of AGA. Androgens have been shown to downregulate BMP2 and BMP4 expression in DPCs, leading to impaired inductive capacity of DPCs and reduced HFSC differentiation. Restoration of BMP2 levels rescues alkaline phosphatase activity, a marker of hair-inductivity in DPCs, and promotes DPC-induced HFSC differentiation, indicating its critical role in maintaining hair follicle regenerative capacity. Notably, BMP signaling may also interact with the Wnt/β-catenin signaling pathway, as evidenced by increased nuclear β-catenin accumulation following BMP2 treatment, suggesting a potential crosstalk between these pathways.⁸⁰ These findings indicate that modulation of BMP-related factors, such as BMP2, may represent a potential therapeutic strategy for AGA treatment.

Hypoxia-Inducible Factor (HIF)-1 Signaling Pathway

Recent transcriptomic analyses have identified the HIF-1 signaling pathway as a novel regulator potentially involved in AGA. HIF-1 pathway-related genes, EGLN1 and EGLN3, have been shown to play important roles in regulating DPC activity, hair growth, and hair cycling. Functional studies indicate that the downregulation of EGLN1 or EGLN3 promotes DPC proliferation and hair growth, prolongs anagen, and delays catagen. Although the role of HIF-1 signaling in AGA remains incompletely understood, current evidence highlights its potential as a novel therapeutic target for modulating hair follicle activity and promoting hair growth.⁴⁰

As described above, we have outlined the key signaling pathways involved in hair biology and their roles in AGA pathogenesis. Recent studies also indicate that these signaling pathways do not act independently but rather interact through extensive crosstalk, which plays a crucial role in hair growth and follicle regeneration.⁸¹ Understanding these intricate signaling dynamics will provide deeper insights into the pathogenesis of AGA and the processes of hair cycling and follicle regeneration. The future trend of exosome therapy for AGA treatment may involve modulating the crosstalk between multiple signaling pathways to restore the dynamic equilibrium disrupted by androgens, by which exosomes may better reverse the pathological process of AGA and achieve hair growth in AGA patients.

Clinical Exploration of Exosome Therapy for Androgenetic Alopecia

The clinical application of exosome-based therapies has emerged as a novel cell-free strategy for AGA treatment and attracted increasing attention. Recent years have seen significant development and translation of exosome-based therapies. Clinical studies carried out so far have provided evidence for applying exosomes in treating AGA (Table 1). Exosomes used in clinical studies for AGA are mainly derived from mesenchymal stem cells (MSCs), which possess strong regenerative properties that can differentiate into various cell types.⁸² Compared with MSC therapy, MSC-derived exosomes (MSC-Exos) retain the therapeutic benefits while minimizing potential risks such as immune rejection and tumorigenicity.^83–85

Table 1.

Clinical Studies on Exosome Therapy for Androgenetic Alopecia Treatment

Author	Year	Study Design	Sample	Source of Exosomes	Treatment Received	Treatment Protocol	Follow-Up Duration	Key Results
Ersan et al86	2024	Prospective study	30M	Foreskin-derived mesenchymal stromal cells	Exosome injection	Single session	12 weeks	7.3 hairs/cm2 increase in hair density (p<0.05); high subjective satisfaction; no severe adverse events
Park et al87	2022	Retrospective study	39 (27M, 12F)	Adipose-derived stem cells	Microneedling + topical exosome application	Weekly for 12 weeks	12 weeks	24.9 hairs/cm2 increase in hair density (p<0.001) and 8.8 µm increase in hair thickness (p<0.001); no severe adverse events
Wan et al88	2025	Prospective Open-Label Study	16M	Adipose-derived mesenchymal stem cells	Microneedling + topical exosome application	Single session	12 months	35 hairs/cm2 increase in hair density; 87% reported satisfaction or high satisfaction; no severe adverse events
Lee et al89	2024	Prospective Open-Label Study	30 (14M, 16F)	Adipose-derived stem cells	Microneedling + topical exosome application	Every week for 3 months, then every 3 weeks for 3 months	24 weeks	8.11 hairs/cm2 increase in hair density (p<0.001); high subjective satisfaction; no severe adverse events

Abbreviations: M, males; F, females.

Preliminary clinical evidence has shown encouraging outcomes in AGA treatment, including improvements in hair density and patient satisfaction, achieved through both injection-based and microneedling-based exosome therapies. For injection-based therapy, a prospective study involving 30 male AGA patients demonstrated that injecting 3 mL of foreskin-derived MSC exosomes (2 mL to the frontal and 1 mL to the vertex region) significantly increased hair density, with sustained patient satisfaction and no reported side effects.⁸⁶ In terms of microneedling-based therapy, several studies have utilized ADSC-Exos. An uncontrolled retrospective study in 39 AGA patients applied ADSC-Exos to the scalp using a microneedle roller once weekly for 12 weeks, resulting in significant increases in hair density and thickness (p<0.05), with no severe adverse reactions aside from needle prickling discomfort during application.⁸⁷ Another prospective, open-label study in 16 male patients applied topical ADSC-Exos following microneedling, reporting an average increase of 35 hairs/cm² at 12 months, high patient satisfaction, and mild side effects (scalp tenderness and irritation) that resolved within 48 hours.⁸⁸ Furthermore, a 2024 prospective study by Ester Lee et al in 30 AGA patients applied topical ADSC-Exos after microneedling treatment, observing significant increases in hair density and improved photographic assessments at 24 weeks, with high subjective satisfaction and no severe adverse reactions.⁸⁹ Collectively, these studies consistently demonstrate that exosome-based therapies improve hair density and thickness with a favorable safety profile.

Importantly, emerging evidence suggests that these clinical benefits are closely associated with the activation of the Wnt/β-catenin signaling pathway. The 2024 prospective clinical study by Ester Lee et al not only demonstrated favorable clinical outcomes but also provided mechanistic insights into this association. In vitro studies reveal that ADSC-Exos activate the Wnt/β-catenin signaling pathway, upregulate hair growth-related genes, promote DPC proliferation, and enhance hair shaft elongation and ALP activity.⁸⁹ These findings provide both preclinical and clinical evidence suggesting the potential of exosome therapy in AGA treatment and indicate that its therapeutic effects are mediated, at least in part, through activation of the Wnt/β-catenin pathway.

Despite the encouraging clinical observations, several critical limitations should be noted. There are few studies published on exosome-based therapies at present, many of which were short-term studies that did not show a long-lasting therapeutic effect or long-term safety of exosomes. Due to limited clinical data, there is a lack of standardized administration protocols and sufficient supporting data. Significant variability exists across studies regarding exosome sources, isolation methods, storage conditions, and formulation protocols, which impedes direct comparison of results and underscores the urgent need for standardized manufacturing and characterization practices. Meanwhile, the clinical studies conducted so far generally have small sample sizes and lack a control group, which means the results should be interpreted cautiously.

Addressing these limitations will be critical for advancing exosome-based therapies toward widespread clinical adoption. In the future, studies with larger sample sizes, longer follow-up periods, and randomized controlled trials are expected to validate dosing regimens of exosomes for clinical application and further validate the long-term efficacy and safety of exosome-based therapies for AGA patients. Further well-designed clinical studies are definitely needed to optimize treatment protocols and better define the therapeutic potential of exosome-based therapies.

Conclusion

AGA is the most common type of hair loss worldwide that affects a substantial proportion of the population, significantly impacting both physical appearance and psychological well-being. Current therapeutic options, including minoxidil and finasteride, are limited by variable therapeutic responses and potential side effects, highlighting the need for alternative therapies. Exosomes, as nano-sized cellular products that mediate intercellular communication, contribute to reversing the pathological process of AGA at the molecular level by targeting the dysregulated signaling pathways in hair follicles of AGA patients. Despite these encouraging advances, current evidence remains limited, and further well-designed studies are required to establish the long-term efficacy, safety, and optimal delivery strategies of exosome therapy. Moreover, addressing challenges in production, application, and regulation is indispensable for promoting the future clinical application of exosome-based therapies in AGA treatment. With continued progress in both basic and translational research, exosome-based interventions may eventually offer new perspectives for the precise and personalized management of AGA.

Disclosure

The authors declare no conflicts of interest in this work.