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Pathophysiological mechanisms of hair follicle regeneration and potential therapeutic strategies

Stem Cell Research & Therapy volume 16, Article number: 302 (2025) Cite this article

Abstract

Androgenetic alopecia (AGA) is a chronic and progressive hair loss disorder marked by follicular miniaturization and a shortened anagen phase. While androgenic and genetic factors contribute to its pathogenesis, increasing evidence highlights the importance of dysregulated molecular signaling in impaired hair follicle (HF) regeneration.

This review explores the interconnected signaling pathways that govern HF cycling and regeneration—Wnt/β-catenin, Sonic Hedgehog (Shh), Bone Morphogenetic Protein (BMP), and Notch. Wnt/β-catenin activation initiates anagen by stimulating stem cell proliferation and follicle formation, while Shh supports follicular proliferation and morphogenesis. Notch regulates HF stem cell (HFSC) fate, and BMP enforces quiescence and catagen onset. Crucially, crosstalk between Wnt-BMP and Shh-Notch pathways ensures follicular homeostasis, highlighting the need to view these pathways as an integrated regulatory network.

Recent therapeutic innovations focus on modulating these signaling cascades. Small molecules such as valproic acid and CHIR99021 activate Wnt signaling; smoothened agonists target Shh; and Noggin mimetics or BMP-neutralizing antibodies inhibit BMP activity. These approaches have shown promising outcomes in preclinical models, including mouse studies, in vitro HFSC systems, etc. Additionally, emerging gene editing technologies (e.g., CRISPR-Cas9) and stem cell–biomaterial integration offer regenerative strategies that move beyond symptomatic treatments like minoxidil or hair transplantation.

Given that AGA is associated with androgen-mediated Wnt suppression and TGF-β activation, targeting these dysregulated networks presents a promising route for long-term management. A deeper understanding of pathway interactions lays the groundwork for precise, durable, and disease-modifying therapies in the evolving landscape of alopecia treatment.

Introduction

Androgenetic alopecia (AGA) is the most prevalent form of hair loss, affecting both men and women, and characterized by progressive follicular miniaturization, a shortened anagen phase, and prolonged telogen duration [1]. This condition significantly impacts patient’s quality of life and presents an ongoing clinical challenge due to limited therapeutic efficacy and incomplete understanding of its molecular underpinnings [2, 3]. Although the role of genetics and androgens is well established, recent advances in molecular biology have shifted the focus toward the intrinsic signaling pathways that govern hair follicle (HF) cycling and regeneration. Understanding these pathways is critical for the development of more targeted and effective treatments for AGA.

This review aims to provide a comprehensive synthesis of the key molecular pathways governing hair follicle regeneration in AGA, with a particular emphasis on their signaling interactions, phase-specific roles, and relevance to therapeutic development. By dissecting the orchestration of these pathways during the hair cycle and highlighting their crosstalk, we provide an integrated framework that may inform novel intervention strategies. Where Wnt/β-catenin, activates HF stem cells (HFSCs) and stimulating hair matrix cell proliferation [4]. Sonic Hedgehog (Shh) promotes HFSC proliferation, supports follicle morphogenesis, and is essential for anagen entry [5]. Notch, Maintains HFSC multipotency and prevents premature differentiation, preserving the stem cell reservoir [6]. Bone Morphogenetic Protein (BMP) enforces HFSC quiescence, suppresses anagen initiation, and drives regression during catagen (regression) and telogen (resting) phases [7]. The hair follicle undergoes cyclic renewal through anagen, catagen, and telogen phases, each governed by dynamic interactions among these pathways. Outlined below is the signaling crosstalk that occurs during each phase of the hair cycle.

In Anagen: Wnt/β-catenin and Shh are upregulated, activating HFSCs and driving proliferation. BMP activity is suppressed, while Notch ensures orderly differentiation [8].

While in Catagen: BMP signaling reactivates, promoting apoptosis and follicle regression. TGF-β antagonizes Wnt, reinforcing catagen entry. Notch and Wnt crosstalk synchronize the balance between proliferation and differentiation [8].

Similarly in Telogen: BMP maintains HFSC dormancy; Notch regulates the stem cell niche to prevent untimely activation. The decline of BMP and reactivation of Wnt/β-catenin signal the transition back to anagen [8].

These pathways do not act in isolation-crosstalk, particularly between Wnt-BMP and Shh-Notch, is critical for temporal and spatial coordination of hair cycling and regeneration.

Beyond these core pathways, additional modulators such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), and transforming growth factor-beta (TGF-β) fine-tune the follicular microenvironment by influencing vascularization, cell proliferation and survival.

In this context, therapeutic strategies targeting these molecular pathways hold promise for reversing or halting the progression of AGA. Small molecules such as valproic acid and CHIR99021, gene therapy, and biologics aimed at modulating Wnt activation, BMP inhibition, or Shh augmentation are under investigation for their regenerative potential [4, 9,10,11,12]. Clinical translation of such therapies requires a nuanced understanding of pathway dynamics, phase-specific modulation, and long-term safety.

Despite significant progress in understanding key signaling pathways involved in hair biology, there are still major gaps in our knowledge about how these pathways interact and are regulated over time during the hair cycle. Disruptions in the delicate balance of these signals can lead to hair follicle abnormalities and hair loss. Recent studies also suggest that these pathways do not act independently, but instead communicate with each other through crosstalk, which plays a crucial role in controlling the hair follicle’s ability to regenerate. The crosstalk is illustrated in Fig. 1.

Fig. 1
figure 1

Crosstalk of all the pathways

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This treatise endeavors to dissect the complex molecular signaling networks implicated in hair follicle regeneration, with a focal emphasis on the principal pathways governing stem cell activity, follicular cycling, and tissue remodeling. By furnishing a comprehensive compendium of these signaling mechanisms, we aspire to delineate prospective therapeutic targets and strategies that can potentiate hair follicle regeneration and proffer innovative modalities for the treatment of hair loss.

In the following sections, we will provide a detailed overview of each signaling pathway, highlighting their mechanistic roles in follicular regeneration, interactions with one another, and implications for clinical intervention. By consolidating current knowledge on signaling crosstalk in hair biology, this review aims to inform future research directions and support the development of targeted therapies for androgenetic alopecia.

Key signaling pathways in hair follicle regeneration

Mechanisms of Wnt/β-Catenin signaling in hair follicle regeneration

The Wnt/β-catenin signaling pathway is a pivotal regulator of hair follicle regeneration, orchestrating the telogen-to-anagen transition, activation of hair follicle stem cells (HFSCs), and tissue repair. (Choi, 2020) In the absence of Wnt ligands, β-catenin undergoes continuous degradation via a destruction complex comprising Axin, APC, and GSK-3β. Upon Wnt ligand engagement with Frizzled receptors, this complex is inhibited, resulting in β-catenin stabilization and nuclear translocation, where it partners with TCF/LEF transcription factors to drive genes critical for HFSC proliferation and differentiation into hair matrix cells [13, 14]. Wnt/β-catenin signaling is essential for both physiological hair cycling and follicular regeneration after injury, as demonstrated in murine and organoid models. Activation of this pathway enhances mitogenic activity and promotes robust follicular repair, supporting its therapeutic potential in wound-induced hair regrowth and alopecia. For instance, Wnt1a and Wnt10b have been shown to accelerate the telogen-to-anagen switch, increase hair shaft elongation, and stimulate dermal papilla cell proliferation in preclinical studies includes mouse models.

Moreover, Wnt signaling maintains the HFSC niche and regulates dermal papilla (DP) function, both of which are essential for initiating hair cycling and post-injury recovery. Dysregulation of this pathway, however, is linked to oncogenic transformation, underscoring the need for precise therapeutic modulation [4, 15, 16]. Collectively, these findings establish Wnt/β-catenin as a central target for clinical strategies aimed at hair follicle regeneration and repair.

Risks and challenges in modulating Wnt signaling

Despite the therapeutic potential associated with the activation of the Wnt/β-catenin signaling pathway, considerable risks are implicated with its excessive stimulation. Chronic or dysregulated activation of Wnt signaling has been associated with the pathogenesis of various tumorigenic processes, including cutaneous malignancies [14]. Hyperactivation of β-catenin can instigate aberrant cellular proliferation and differentiation, thereby contributing to the oncogenic development of neoplasms such as basal cell carcinoma and squamous cell carcinoma [17].

Furthermore, the multifaceted nature of Wnt signaling across diverse biological processes and tissue types necessitates those therapeutic strategies be meticulously tailored to minimize unintended adverse effects. For instance, localized delivery mechanisms for Wnt activators or the application of selective Wnt modulators may represent a more prudent approach for hair follicle regeneration, effectively mitigating the risk of unchecked cellular proliferation. This precision-driven methodology underscores the imperative for exactitude in therapeutic interventions aimed at leveraging Wnt signaling for regenerative applications while concurrently safeguarding against oncogenic ramifications.

Mechanism of Sonic Hedgehog (Shh) signaling in hair follicle morphogenesis and regeneration

The Sonic Hedgehog (Shh) signaling pathway is a critical regulator of hair follicle (HF) morphogenesis, cycling, and regeneration [5]. Activation of this pathway begins when Shh ligands bind to the Patched (Ptch) receptor, relieving inhibition on Smoothened (Smo) and initiating downstream signaling [18]. This cascade leads to the dissociation of Suppressor of Fused (SUFU) from Gli transcription factors, allowing Gli1, Gli2, and Gli3 to translocate to the nucleus and regulate gene expression involved in cell proliferation, differentiation, and HF stem cell (HFSC) activation [18].

Shh signaling is essential for the telogen-to-anagen transition and for maintaining the proliferative capacity of HFSCs in both embryonic and adult skin. In adult mice, blockade of Shh signaling with neutralizing antibodies halts anagen initiation and impairs hair regrowth, while exogenous Shh administration can induce anagen and stimulate follicular regeneration. Gli1 + and LGR5 + HFSCs, regulated by Shh, are localized to the bulge and outer root sheath, contributing to both follicle maintenance and regeneration during the hair cycle [19].

Shh activity in the dermal papilla coordinates epithelial-mesenchymal interactions necessary for hair shaft formation and follicular homeostasis [20, 21]. Furthermore, Shh pathway activation in wound environments reinstalls a regenerative dermal niche, enabling new follicle neogenesis and repair, as demonstrated in murine and organoid models.

Precise regulation of Shh-Gli signaling is required; dysregulation can result in impaired follicular integrity or tumorigenesis. Thus, understanding the Shh pathway is fundamental for the development of targeted therapies for alopecia and hair follicle regeneration [22].

Mechanism of Notch signaling in hair follicle stem cell fate

Notch signaling regulates hair follicle stem cell (HFSC) fate by maintaining a balance between self-renewal and differentiation. Activation occurs when Notch receptors on HFSCs bind to Jagged or Delta-like ligands on adjacent cells, triggering proteolytic cleavage and release of the Notch intracellular domain (NICD) [23, 24]. The NICD translocates to the nucleus and interacts with RBP-Jκ (CSL) transcription factors, inducing expression of genes that preserve stem cell multipotency and inhibit premature differentiation [25].

Within the hair follicle, Notch activity is critical in the bulge region, where it prevents early progenitor differentiation and maintains the stem cell reservoir necessary for regeneration and proper cycling [26]. Disruption of Notch signaling leads to stem cell depletion and impaired follicle regeneration. Notch also interacts with Wnt, BMP, and Shh pathways, integrating signals that coordinate hair follicle development and homeostasis.

Notch-Wnt signaling interactions

The intricate interplay between Notch and Wnt signaling pathways has been demonstrated to regulate the fate of hair follicle stem cells (HFSCs), with Notch signaling typically exerting an inhibitory effect on Wnt activity to forestall the premature activation of hair growth [27]. Conversely, Wnt signaling facilitates the differentiation of progenitor cells into specific hair follicle lineages, while Notch activity ensures that only suitably poised progenitor cells undergo differentiation during the anagen phase, thereby preserving the regenerative potential of the follicle. This delicate balance between Notch and Wnt signaling is essential for orchestrating the temporal dynamics of hair follicle development and cycling, ensuring that hair follicle homeostasis is maintained throughout the organism’s life cycle. The regulatory mechanisms governing this interplay are critical for preventing aberrant differentiation and optimizing hair follicle regeneration.[ 28].

Notch-BMP interactions

Bone Morphogenetic Proteins (BMPs) are integral to regulating hair follicle regression during the catagen phase and maintaining follicular quiescence throughout the telogen phase. Notch signaling interacts with BMP pathways to modulate hair follicle cycling, with BMP signaling predominantly exerting inhibitory effects on hair growth while Notch signaling fine-tunes the responsiveness of progenitor cells to BMP-induced quiescence [24]. This interaction is crucial for maintaining a delicate balance between hair follicle activation and dormancy, which is essential for the long-term functionality and regenerative capacity of hair follicles. The coordinated regulation of these pathways is vital for ensuring optimal hair follicle cycling and preventing aberrant growth patterns.

Notch-Shh cross-talk

The Sonic Hedgehog (Shh) signaling pathway is instrumental in orchestrating the early stages of hair follicle development and in sustaining the integrity of the dermal papilla [29]. Notch and Shh signaling pathways engage in a reciprocal interaction within hair follicle stem cell niches, where Notch signaling modulates Shh expression to influence the differentiation trajectories of follicular progenitor cells [30]. This intricate cross-talk is essential for proper follicle morphogenesis, as both pathways are integral to the maintenance, proliferation, and differentiation of stem cells. Such interactions ensure that the dynamic balance between stem cell renewal and differentiation is precisely regulated, facilitating optimal hair follicle development and function.

Mechanisms of BMP signaling in hair follicle cycling

Bone Morphogenetic Proteins (BMPs) primarily exert their functions by binding to BMP receptors located on the cellular surface, which subsequently activates intracellular SMAD signaling cascades [31]. Upon activation, SMAD proteins translocate to the nucleus, where they modulate the expression of target genes implicated in cellular growth, differentiation, and apoptosis [32]. In the context of hair follicle cycling, BMP signaling assumes distinct roles during the anagen and catagen phases, which are critical for hair growth regulation.

Growth (Anagen Phase): During the anagen phase, BMP signaling is suppressed to facilitate the proliferation of hair follicle stem cells (HFSCs), which subsequently differentiate into mature follicular cell types [33]. The inhibition of BMP activity is essential for initiating hair follicle development and promoting growth, thereby enabling the transition from the telogen to the anagen phase.

Regression (Catagen Phase): Conversely, BMP signaling is activated during the catagen phase to induce hair follicle regression [34]. This phase is characterized by programmed apoptosis and follicular shrinkage, culminating in the cessation of hair growth. BMP signaling is crucial for orchestrating follicular involution, thereby preparing the follicle for subsequent cycles.

Dysregulation of BMP signaling can lead to aberrant hair follicle cycling, resulting in conditions such as alopecia or follicular miniaturization [35]. The precise modulation of BMP activity is thus vital for maintaining normal hair follicle function and regenerative capacity throughout the hair cycle.

BMP antagonists: regulators of hair follicle regeneration

Beyond the activation of BMP receptors, BMP modulation via specific antagonists significantly regulates hair follicle regeneration. Noggin and Gremlin, two key BMP antagonists, are crucial regulators of hair follicle function and regeneration [36].

Noggin

Noggin, a well-characterized BMP antagonist, binds BMP ligands, preventing their receptor interaction [37]. (Groppe 2002) By inhibiting BMP signaling, Noggin promotes hair follicle regeneration and anagen initiation. Noggin expression upregulates during early anagen in response to hair follicle activation, and its inhibition causes hair follicle development defects and premature regression. [38.

]Noggin is particularly important for hair follicle stem cell (HFSC) regulation. By blocking BMP inhibitory effects, Noggin enables stem cell proliferation and differentiation into specialized follicular cell types [39]. The balance between BMP signaling and Noggin activity is essential for maintaining a healthy hair cycle and preventing hair loss.

Gremlin

Like Noggin, Gremlin is another BMP antagonist that sequesters BMP ligands, preventing their interaction with BMP receptors [40]. Gremlin critically functions in early hair follicle regeneration, particularly following injury. Overexpression of Gremlin enhances hair growth and regeneration in experimental models, while Gremlin suppression reduces hair follicle activity and impairs follicular regeneration [41].

Gremlin’s ability to modulate BMP signaling is essential for hair follicle reactivation during anagen. Studies suggest that Gremlin expression is regulated by various signaling pathways, including Wnt signaling, involved in initiating the hair growth phase [42]. Along with Noggin, Gremlin fine-tunes BMP signaling and supports hair follicle regeneration after injury or during normal hair cycling.

The importance of Fine-Tuned BMP signaling in follicle cycling

The equilibrium between BMP activation and inhibition is paramount for maintaining follicular homeostasis. Excessive BMP signaling can precipitate premature follicle regression during the anagen phase, whereas insufficient BMP activity may hinder follicular involution during the catagen phase, resulting in prolonged follicular growth and atypical hair growth patterns [43].

Numerous factors, including external stimuli, genetic determinants, and environmental influences, intricately govern the precise regulation of BMP signaling [44]. For instance, dermal papilla cells, which serve as pivotal signaling hubs within the hair follicle, are known to synthesize both BMP ligands and their antagonists, thereby contributing to the modulation of the hair cycle [45]. Additionally, tissue injury and physiological stress can activate BMP signaling pathways as part of a wound healing response, further emphasizing the necessity for meticulous control of this pathway.

Dysregulation of BMP signaling can lead to a variety of pathological conditions associated with hair loss and abnormal hair growth, including androgenetic alopecia and cicatricial alopecia [46]. A comprehensive understanding of the mechanisms that regulate BMP signaling and its antagonism is essential for devising potential therapeutic strategies aimed at addressing these conditions.

Therapeutic implications of BMP signaling modulation

Given the pivotal role of BMP signaling in regulating hair follicle cycling, targeted modulation of this pathway presents a promising therapeutic avenue for addressing hair loss conditions. BMP antagonists, notably Noggin and Gremlin, have emerged as potential agents for promoting hair follicle regeneration and stimulating hair growth.

Recent investigations have focused on the development of small molecule inhibitors and gene therapy strategies aimed at modulating BMP signaling, either by attenuating BMP activity or enhancing the function of BMP antagonists [47]. These therapeutic modalities seek to restore the delicate equilibrium between BMP activation and inhibition, thereby fostering hair follicle regeneration and promoting hair growth in individuals afflicted with hair loss disorders.

However, meticulous consideration must be given to the potential adverse effects associated with BMP signaling modulation. Given the extensive array of physiological processes governed by BMPs—including bone formation and tissue repair—any therapeutic intervention targeting this pathway must be precisely calibrated to avert unintended consequences, such as tumorigenesis or abnormal tissue proliferation. This underscores the necessity for a nuanced understanding of BMP signaling dynamics to ensure safe and effective therapeutic applications in the context of hair restoration.

Mechanism of AKT/MAPK signaling pathway in hair follicle regeneration

The phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways represent pivotal intracellular signaling cascades that govern a diverse array of cellular processes, encompassing proliferation, survival, and differentiation.[48.

]These pathways are indispensable for maintaining the dynamic equilibrium of hair follicle cycling and regeneration. Within the context of hair follicle physiology, AKT and MAPK are essential for stem cell maintenance, follicular growth, and the transitions between distinct hair cycle phases [49]. The PI3K-AKT/Wnt-β-Catenin pathways are strongly associated with HFSC activation and HF formation. Enrichment of MAPK suggests the role of IGF2 in promoting anagen via MAPK signaling.

8.1 AKT signaling in hair follicle stem cell (HFSC) maintenance and follicular function

AKT signaling is integral to the regulation of a spectrum of cellular functions, encompassing cell survival, metabolism, and growth, and it plays a particularly salient role in the pathophysiology of hair follicle stem cells (HFSCs). The pathway is activated in response to various extracellular stimuli, including growth factors such as insulin-like growth factor (IGF), epidermal growth factor (EGF), and fibroblast growth factors (FGFs) [50]. The activation of AKT leads to the phosphorylation of downstream targets that govern critical processes such as cell cycle progression, inhibition of apoptosis, and modulation of cellular metabolism.

The AKT signaling plays several crucial roles in the context of anatomy of the hair follicle:

Regeneration and maintenance of stem cells

AKT is pivotal for the maintenance of HFSCs residing within the bulge region of the hair follicle. Through its regulation of cellular proliferation and survival, AKT signaling ensures the availability of HFSCs for regeneration throughout the hair cycling process, particularly during the transition from telogen (resting phase) to anagen (growth phase) [51].

Anagen initiation

During the transition from telogen to anagen, AKT signaling facilitates the activation and proliferation of HFSCs, thereby underpinning the regeneration of hair follicles. This transition is critical for hair follicle functionality, as it permits the follicle to enter the growth phase characterized by hair fiber production.[51.

]Dermal Papilla Function: The dermal papilla (DP), a central signaling nexus within the hair follicle, orchestrates the proliferation and differentiation of follicular cells. AKT signaling also plays a crucial role in modulating dermal papilla cell function by enhancing their proliferative capacity and facilitating interactions with stem cells. This interplay is essential for establishing and sustaining the hair growth cycle [51].

Thus, AKT activation is vital not only for stem cell survival and proliferation but also for the regenerative potential of the entire hair follicle. Dysregulation of AKT signaling, whether through overactivation or inhibition, can disrupt hair cycling dynamics, impair regeneration, and contribute to hair loss disorders [52]. Understanding these mechanisms offers insights into potential therapeutic interventions aimed at restoring normal hair follicle function.

MAPK signaling in hair follicle differentiation and regeneration

The Mitogen-Activated Protein Kinase (MAPK) pathway, also referred to as the ERK1/2 pathway, represents a critical signaling cascade integral to the regulation of hair follicle differentiation and morphogenesis [53]. This pathway is activated by diverse extracellular signals, including growth factors, cytokines, and hormones, and it primarily governs gene expression, cellular differentiation, and proliferation.

  1. 1.

    Gene Expression Regulation: MAPK signaling facilitates the activation of transcription factors that modulate gene expression patterns essential for hair follicle differentiation and morphogenesis. Notably, activator protein 1 (AP-1) and c-Fos are activated downstream of MAPK and play a pivotal role in mediating the effects of MAPK signaling on follicular differentiation [54].

  2. 2.

    Follicle Differentiation: The MAPK pathway orchestrates the differentiation of cells within the hair matrix and other follicular compartments. It regulates the transition of progenitor cells into differentiated keratinocytes that contribute to hair shaft formation. Furthermore, MAPK signaling is crucial for regulating hair follicle morphology throughout various stages of the hair cycle, ensuring proper follicular development and growth [55].

  3. 3.

    Regenerative Potential: MAPK signaling is implicated in the regeneration of damaged hair follicles. Following injury or wounding, the MAPK pathway is activated to promote repair processes, including stem cell activation and restoration of follicular structure. This regenerative capacity renders MAPK signaling an attractive therapeutic target for stimulating hair regrowth in conditions characterized by follicular damage [56].

  4. 4.

    Interaction with AKT Signaling: The MAPK and AKT pathways interact at multiple levels to coordinate the overall regenerative process. MAPK signaling can regulate AKT activation through the phosphorylation of upstream components such as phosphoinositide 3-kinase (PI3K), leading to synergistic effects on stem cell proliferation and hair follicle regeneration. This crosstalk enhances the overall proliferative response of hair follicle cells and optimizes the regenerative capacity of the follicle. Understanding these intricate signaling dynamics is essential for developing targeted therapies aimed at promoting hair follicle health and function [57].

Dysregulation of AKT/MAPK signaling and hair loss

Dysregulation of the AKT and MAPK signaling pathways is implicated in various forms of hair loss, with abnormal signaling in these cascades leading to several pathological consequences:

  1. 1.

    Premature Hair Follicle Regression: Overactivation of AKT signaling has been correlated with the premature regression of hair follicles and abnormal cycling dynamics. Conversely, inhibition of AKT activity may hinder the activation of stem cells, resulting in delayed follicular regeneration [58].

  2. 2.

    Impaired Stem Cell Function: Aberrant MAPK signaling can disrupt the proper differentiation of hair follicle stem cells (HFSCs), leading to defective hair follicle development or miniaturization. In conditions such as androgenetic alopecia, hyperactive MAPK signaling may drive excessive differentiation of progenitor cells, thereby limiting the regenerative capacity of the follicle [59].

  3. 3.

    Anagen Arrest: In certain forms of hair loss, dysregulated AKT or MAPK signaling may culminate in the failure to transition into the anagen phase, causing prolonged telogen and cessation of hair growth. This phenomenon is particularly relevant in contexts where inflammatory cytokines or environmental stressors activate MAPK signaling, thereby disrupting normal follicular cycling [60].

  4. 4.

    Fibrosis and Scarring: In specific pathological conditions, excessive MAPK signaling may contribute to fibrosis and scarring within the dermal papilla, disrupting follicular function and impairing hair growth. This process is often observed in conditions such as cicatricial alopecia, where scar tissue replaces normal follicular structures [38].

Therapeutic potential of AKT/MAPK pathway modulation

The AKT and MAPK signaling pathways represent compelling targets for therapeutic interventions aimed at ameliorating hair loss disorders. The strategic application of small molecule inhibitors or activators of these pathways holds the potential to modulate hair follicle function and stimulate hair regrowth across various conditions, including androgenetic alopecia, telogen effluvium, and alopecia areata.

  1. 1.

    AKT Pathway Modulation: The activation of AKT signaling within hair follicle stem cells (HFSCs) has been proposed as a viable strategy to enhance follicular regeneration. Specifically, the employment of AKT agonists or gene therapy approaches designed to activate AKT in stem cells may augment stem cell proliferation and promote hair growth. Conversely, the inhibition of AKT signaling could be considered a potential strategy for managing excessive hair growth or addressing cancer-related hypertrichosis [61].

  2. 2.

    MAPK Pathway Modulation: In conditions characterized by hyperactive MAPK signaling that precipitates premature hair follicle differentiation or fibrosis, the utilization of MAPK inhibitors may offer therapeutic potential. Conversely, the activation of MAPK signaling in scenarios where hair growth is impaired could stimulate the proliferation and differentiation of stem cells, thereby promoting hair regeneration [62].

  3. 3.

    Combined Approaches: Given the intricate cross-talk between the AKT and MAPK pathways, combined therapeutic strategies targeting both signaling cascades may yield synergistic effects in enhancing hair regeneration. For instance, concurrently administering AKT activators alongside MAPK inhibitors could optimize the balance between cellular proliferation, differentiation, and follicular regeneration. Such multifaceted approaches may provide a robust framework for developing effective treatments aimed at restoring hair follicle health and function in individuals suffering from various forms of alopecia [63].

Crosstalk between all the pathways

The intricate interplay between the Notch, BMP, Wnt, AKT, and Shh signaling pathways orchestrates a multifaceted regulatory network that governs critical cellular processes such as differentiation, proliferation, and tissue homeostasis.

BMP signaling, mediated by R-Smad/Co-Smad complexes, exhibits a context-dependent ability to either enhance or inhibit Wnt signaling [31]. This regulation is achieved by modulating the availability of β-catenin or its interaction with transcriptional co-factors like LEF/TCF. Interestingly, Noggin, a well-known BMP inhibitor, can indirectly amplify Wnt signaling by stabilizing β-catenin, thereby promoting processes such as hair follicle development and regeneration [36].

The interplay between Wnt and AKT signaling underscores their interconnected nature. Wnt signaling stabilizes β-catenin by inhibiting GSK3β, a critical regulatory target al.so involved in the PI3K/AKT pathway [48, 49]. This shared target emphasizes their synergistic roles in supporting cell survival and growth. Notably, AKT signaling, activated by mediators like VEGF and PI3K, further amplifies Wnt signaling by suppressing GSK3β activity. This inhibition enhances β-catenin stabilization, driving the transcriptional activation of Wnt target genes.

The relationship between Shh and BMP/Wnt signaling is equally intricate; Shh signaling activates Gli transcription factors that can upregulate or downregulate components of both BMP and Wnt pathways. Notably, BMP signaling can antagonize Shh activity by promoting the repression of Gli transcription factors via Sufu, while Wnt signaling often synergizes with Shh to facilitate tissue-specific responses [64].

Notch signaling regulates BMP pathway activity via R-Smad modulation, exerting bidirectional control over BMP-responsive transcription [24]. Through NICD-Smad interaction, Notch refines HFSC fate by integrating Wnt and TGF-β signaling, counteracting BMP-mediated Wnt inhibition [27, 28]. This crosstalk positions Notch as a key regulator of follicular morphogenesis, balancing HFSC quiescence, activation, and differentiation, with implications for hair regeneration and therapeutic strategies. Figure 2 illustrates the interaction between these signaling pathways.

Fig. 2
figure 2

Detailed crosstalk of signaling pathways

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Limitations and future directions in hair follicle regeneration therapies

Traditional therapies for alopecia include pharmacotherapy (e.g., minoxidil, finasteride), low-level laser therapy (LLLT), and hair transplantation. Minoxidil promotes vasodilation and prolongs anagen phase [65], whereas finasteride reduces DHT levels by inhibiting 5α-reductase, thus minimizing follicular miniaturization. While both are FDA-approved and widely used, limitations include variable efficacy, the need for long-term use, and side effects such as hypotension or sexual dysfunction.

LLLT stimulates mitochondrial activity and enhances cell metabolism in dermal papilla cells. It is non-invasive and generally well-tolerated, but requires consistent, prolonged use for visible results, and its efficacy varies across patients [66,67,68].

Hair transplantation offers a permanent solution by relocating follicles from androgen-insensitive regions. While effective in suitable candidates, it is invasive, expensive, and requires surgical expertise [69, 70]. Furthermore, the success of graft survival and aesthetic outcome varies depending on donor site quality and technique used [71].

These therapies, while beneficial, do not directly address the molecular causes of follicular dysfunction. Integrating them with pathway-targeted approaches may offer synergistic benefits in future treatment paradigms.

Limitations in current therapeutic approaches

The advancement of therapeutic modalities targeting hair follicle regeneration has been impeded by multifaceted limitations inherent in the modulation of pivotal signaling cascades, including Wnt/β-catenin, AKT/MAPK, Shh, and Notch.

  1. 1.

    Adverse Effects and Safety Considerations: A primary constraint of numerous pathway-targeting strategies is the propensity for adverse effects. Unchecked or excessive activation of pathways such as Wnt/β-catenin may precipitate tumorigenesis or follicular dysplasia. Similarly, dysregulated AKT/MAPK signaling could incite aberrant cellular proliferation, heightening the risk of malignant transformation or other pathological states. The challenge of achieving precise modulation without eliciting such deleterious effects presents a formidable barrier to the clinical translation of these therapies.

  2. 2.

    Efficacy Limitations in Chronic Alopecias: Despite preliminary studies and in vivo models demonstrating the regenerative capabilities associated with specific pathway modulation, clinical efficacy in human cohorts—especially concerning chronic alopecia conditions like androgenetic alopecia and alopecia areata—remains largely unsubstantiated due to a dearth of primary evidence. The intricate nature of hair follicle regeneration, influenced by a confluence of genetic, environmental, and hormonal factors, complicates the establishment of reliable therapeutic outcomes.

  3. 3.

    Insufficient Long-Term Data: Many therapeutic interventions—including gene editing, microRNA applications, and biologic agents—are still undergoing initial clinical evaluations. Consequently, the long-term safety, efficacy, and sustainability of hair regrowth post-treatment are inadequately documented. Comprehensive longitudinal studies with substantial sample sizes are imperative to ascertain whether induced regeneration is enduring or necessitates ongoing therapeutic intervention for sustained results.

  4. 4.

    Challenges in Stem Cell-Based Interventions: While stem cell therapies present significant promise for hair follicle regeneration, they confront substantial hurdles regarding cellular sourcing, potential immune rejection, and the differentiation processes required to convert stem cells into functional hair follicle cells. The in vivo behavior of transplanted stem cells can exhibit unpredictability, with risks including tumorigenesis or incomplete differentiation into the requisite follicular lineage.

  5. 5.

    Complexity of Hair Follicle Regeneration Mechanisms: Hair follicle regeneration epitomizes a dynamic and multifactorial process governed by an array of interlinked signaling networks and localized microenvironmental factors alongside systemic regulators. The challenge lies in selectively targeting individual pathways without disrupting the intricate crosstalk between Wnt, Notch, BMP, and other regulatory cascades. Oversimplification in therapeutic approaches that focus solely on isolated pathways may jeopardize follicular homeostasis and regenerative capacity. Thus, a balanced approach integrating both strategies may be optimal for future therapeutic endeavors.

Conclusion and future directions

Although different forms of alopecia are driven by distinct signaling disruptions. Androgenetic alopecia (AGA), the focus of this review, involves androgen-induced suppression of Wnt/β-catenin and activation of TGF-β pathways leading to follicular miniaturization. In contrast, alopecia areata (AA) involves autoimmune mechanisms and JAK-STAT pathway activation. While telogen effluvium and cicatricial alopecia implicate other signaling axes, they remain beyond the scope of this review. Understanding these differences supports the development of more targeted, condition-specific therapies.

Regenerative medicine modalities such as biomimetic polypeptides, exosome-based therapies, and stem cell interventions represent the most promising emerging options for androgenetic alopecia, though they remain in early stages of clinical development. Importantly, future therapeutic strategies may benefit from integrating these approaches to target multiple signaling pathways simultaneously, thereby enhancing follicular regeneration and improving clinical outcomes. Rigorous clinical trials are essential to validate these integrated, multi-pathway therapies and fully realize their potential in hair restoration although preclinical studies evidence supports the efficacy of targeted modulation of these pathways.

Importantly, multi-pathway strategies have shown superior outcomes compared to monotherapies, reflecting the integrated nature of follicular signalling that should incorporate pharmacologic agents, molecular therapies, and regenerative technologies such as stem cell transplantation and tissue engineering to achieve durable restoration.

Future therapeutic paradigms for hair follicle regeneration are anticipated to pivot towards personalized methodologies, leveraging genomic profiling and patient-specific biomarkers to customize interventions predicated on the unique pathophysiological mechanisms underlying various conditions of alopecia. Innovations in small molecule therapeutics such as valproic acid and CHIR99021 and biologic agents will be directed at the precise modulation of critical signaling pathways, thereby enhancing both safety and therapeutic efficacy. The advent of gene editing technologies, particularly CRISPR-Cas9, holds promise for rectifying genetic aberrations, while the integration of stem cell-based therapies with tissue engineering approaches may facilitate the restoration or regeneration of hair follicles in advanced cases.

Given the heterogeneous etiologies of alopecia—including hormonal, genetic, and immune-mediated factors—a multidisciplinary framework is essential. Collaborative engagement among dermatologists, endocrinologists, gynaecologists, and allied specialists will be critical for delivering comprehensive and personalized care.

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Acknowledgements

The concept for this manuscript was developed by Dr. Depti Bellani and Dr. Raji Patil. The manuscript writing and diagram preparation were carried out by Mr. Ashwin Prabhughate and Ms. Riya Shahare. The final validation was conducted by Dr. Debraj Shome, Dr. Rinky Kapoor, and Dr. Michael Gold. The Author declare that they have not use AI-generated work in this manuscript.

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Authors and Affiliations

  1. Department of Medical Affairs, QR678, Esthetic Centers International Pvt Ltd, Mumbai, Maharashtra, India

    Depti Bellani & Raji Patil

  2. Department of Research, The Esthetic Clinics, Mumbai, Maharashtra, India

    Ashwin Prabhughate & Riya Shahare

  3. Gold Skin Care Center, Tennessee Clinical Research Center, Nashville, Tennessee, USA

    Michael Gold

  4. Department of Dermatology, Cosmetic Dermatology & Dermato-Surgery, The Esthetic Clinics, Mumbai, Maharashtra, India

    Rinky Kapoor

  5. Department of Facial Plastic Surgery and Facial Cosmetic Surgery, The Esthetic Clinics, Mumbai, Maharashtra, India

    Debraj Shome

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Bellani, D., Patil, R., Prabhughate, A. et al. Pathophysiological mechanisms of hair follicle regeneration and potential therapeutic strategies. Stem Cell Res Ther 16, 302 (2025). http://doi.org/10.1186/s13287-025-04420-4

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Stem Cell Research & Therapy

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