Targeting Inflammation and Vascular Dysfunction in Androgenetic Alopecia: Emerging Therapeutic Opportunities and Future Perspectives

1. Introduction

Hair follicles are highly dynamic mini-organs that undergo repeated cycles of growth, regression and regeneration throughout life [1,2]. These cyclic changes are accompanied by coordinated remodeling of the perifollicular vasculature, which supplies the oxygen and nutrients required for follicular growth [3,4]. Perifollicular vascularization increases during anagen, when follicles are metabolically and proliferatively active, and regresses during catagen and telogen [3]. Consistent with a functional role for this vascular remodeling, experimental overexpression of vascular endothelial growth factor (VEGF) increased perifollicular vascularization, accelerated hair growth and enlarged hair follicles in mice [3]. More recent evidence further indicates that endothelial cells (ECs) and dermal papilla cells (DPCs) engage in reciprocal signaling that coordinates angiogenesis with hair follicle regeneration [5]. Therefore, the perifollicular vasculature is not only a passive supply network but also an active component of the hair follicle niche [3,5].

Androgenetic alopecia (AGA) is the most common form of non-scarring hair loss, with prevalence increasing with age [6]. It is characterized by progressive miniaturization of susceptible hair follicles, resulting in the production of progressively shorter, thinner and less pigmented hairs [7,8]. Clinically, men typically develop frontotemporal recession and vertex hair loss, whereas women more commonly exhibit diffuse thinning over the central scalp with relative preservation of the frontal hairline [6]. Beyond its physical manifestations, AGA can adversely affect body image, self-confidence and quality of life [9].

The best-established mechanism underlying AGA is genetically determined susceptibility to androgen signaling [7,8]. Dihydrotestosterone (DHT), generated from testosterone by 5α-reductase, binds androgen receptors in susceptible DPCs and alters their paracrine signaling to surrounding follicular cells [8]. These changes shorten the anagen phase and contribute to progressive follicular miniaturization [7,8]. The clinical efficacy of finasteride, which inhibits type II 5α-reductase and reduces DHT levels in the scalp and serum, provides strong evidence for the central role of androgen signaling in male AGA [10,11]. However, androgen-dependent signaling alone may not fully account for the broader remodeling of the follicular microenvironment observed in AGA, including inflammatory, fibrotic and vascular alterations [8,12].

Histological studies have identified low-grade inflammatory infiltrates around affected follicles, particularly within the infundibular and isthmic regions [13,14]. Perifollicular inflammation is also associated with increased collagen deposition and fibrosis in AGA scalp samples [12,15]. Such alterations could impair the cellular and extracellular signals required to maintain normal follicular cycling and regeneration, though whether they contribute directly to follicular miniaturization or arise secondary to the disease process remains uncertain [8,12]. Importantly, inflammation and fibrosis may also influence the local vasculature, raising the possibility that these components of the follicular microenvironment are functionally interconnected rather than independent pathological features.

Vascular alterations provide another potential link between microenvironmental remodeling and impaired follicular growth [4,16,17]. Early clinical studies reported reduced subcutaneous blood flow and lower oxygen partial pressure in balding scalp compared with hair-bearing or control scalp [16,17]. Experimental studies provide biological plausibility for a functional consequence of impaired perfusion. In ischemic skin models, reduced blood supply delays hair growth and decreases hair-shaft diameter and hair density [4]. However, these models do not reproduce the genetically determined and androgen-dependent pathogenesis of human AGA, and the available clinical studies are largely associative [4,8]. Consequently, reduced perfusion cannot yet be considered an established cause of follicular miniaturization [16,17].

A major unresolved question is therefore whether vascular dysfunction actively contributes to AGA progression, develops secondarily as follicles miniaturize and their metabolic demands decline, or participates in a reciprocal process involving DPCs, ECs, immune cells and the extracellular matrix [3,5,8]. This review examines the physiological functions of the perifollicular vascular niche and critically evaluates evidence linking vascular alterations to inflammation, fibrosis and follicular miniaturization in AGA. We further discuss current and emerging therapeutic approaches that may modulate these interconnected components of the follicular microenvironment and highlight the key mechanistic and clinical evidence required before vascular- and inflammation-targeted strategies can be translated into effective treatments for AGA.

Literature Search Strategy

A literature search was performed in PubMed to identify studies related to AGA, inflammation, vascular function, the hair follicle microenvironment, and emerging therapeutic strategies. The search mainly included studies published between January 2000 and 17 September 2026. Search terms included combinations of “androgenetic alopecia”, “hair follicle”, “inflammation”, “vascular dysfunction”, “angiogenesis”, “dermal papilla cells”, “endothelial cells”, “hair follicle stem cells” and “drug delivery”. English-language peer-reviewed original studies and review articles were considered. Original studies were prioritized when specific experimental or clinical findings were discussed. Earlier studies published before 2000 were also included when they provided important evidence for hair follicle biology, vascular regulation or established AGA treatments. This article was designed as a narrative review rather than a systematic review.

2. Hair Follicle Microenvironment in AGA

Alopecia refers to a group of disorders that cause partial or complete hair loss and can be broadly divided into non-scarring and scarring forms [18]. In non-scarring alopecia, the hair follicle is not permanently destroyed, so hair regrowth may still be possible when the underlying cause is controlled [18]. Scarring alopecia, also known as cicatricial alopecia, involves permanent destruction of the hair follicle and its replacement by fibrotic tissue [19,20]. Damage to the bulge region is especially important because this region contains epithelial hair follicle stem cells (HFSCs) required for long-term follicular regeneration [19,20].

AGA is classified as non-scarring alopecia because affected follicles undergo progressive miniaturization but are not normally replaced by permanent scars [6,21]. Affected follicles can exhibit low-grade perifollicular inflammation [13,15], altered extracellular matrix deposition and localized fibrosis without complete destruction of the HFSC niche [12,15]. However, it remains uncertain whether these changes actively promote follicular miniaturization or develop during long-term disease progression [12].

2.1. Structure and Physiological Regulation of the Hair Follicle

2.1.1. Hair Follicle Structure and Stem Cell Niche

The mature hair follicle can be broadly divided into a permanent upper region and a lower, cycling region that undergoes repeated growth, regression, and regeneration during successive hair cycles [22,23]. Within the permanent region, the bulge serves as a major epithelial stem cell niche and contains relatively quiescent HFSCs that sustain long-term follicular regeneration [22,24]. During telogen, most bulge HFSCs remain quiescent until signals associated with the transition to anagen promote their activation [22,25]. Immediately below the bulge lies the secondary hair germ, a population of epithelial progenitor cells that responds rapidly to inductive signals at anagen onset and contributes to regeneration of the lower follicle [25].

Regeneration of the cycling portion of the follicle depends on coordinated signaling between epithelial cells and the underlying mesenchymal niche. At the base of the follicle, the dermal papilla (DP) is a specialized mesenchymal structure composed of DPCs embedded within an extracellular matrix [1,26]. The DP provides inductive signals that regulate follicular growth and cycling. The number of DPCs can alter hair size, shape and regenerative capacity [27]. During anagen, rapidly proliferating matrix cells surround the DP and subsequently differentiate to generate the hair shaft and inner root sheath (IRS) [1,22]. These structures are enclosed by the outer root sheath (ORS), which is continuous with the upper permanent portion of the follicle and contains epithelial populations involved in follicular growth and regeneration [22,28]. Thus, normal hair cycling depends on coordinated interactions among epithelial stem and progenitor populations, their differentiated descendants, and the DP mesenchymal niche.

The DP is also closely integrated with the perifollicular vascular niche. A capillary network surrounds the lower follicle and undergoes dynamic remodeling in parallel with the hair cycle [3,29]. Recent studies suggest that ECs participate directly in the regulation of follicular activity rather than functioning solely as a source of oxygen and nutrients. Capillary ECs preferentially communicate with DPCs during normal hair cycling, with C-C motif chemokine ligand 2 (CCL2) implicated in this interaction [29]. Importantly, DPCs are not only supported by ECs but can also actively regulate endothelial activity [30]. DPCs increased the endothelial release of VEGF and IGF-1, which may further support vascular remodeling around the hair follicle [30]. These findings support bidirectional communication between DPCs and ECs within the follicular niche [30]. However, this evidence was obtained from an in vitro co-culture model and has not yet been confirmed in human AGA scalp [30].

In addition, reciprocal metabolic signaling between ECs and DPCs has been identified as a mechanism coordinating angiogenesis with hair regeneration [5]. EC-derived endothelin 1 (EDN1) activates endothelin receptor type A (EDNRA) on DPCs and promotes taurine metabolism, whereas DP-derived cardiotrophin 1 (CTF1) signals through interleukin-6 signal transducer (IL6ST) on ECs to promote α-linolenic acid metabolism and angiogenic activity [5]. Regenerative factors derived from adipose-derived stem cells may also support the follicular microenvironment. Topical adipose-derived stem cell constituent extract increased hair count and hair-shaft diameter in patients with AGA, suggesting that stem cell-derived paracrine factors may promote follicular growth and tissue regeneration [31]. These reciprocal signaling pathways illustrate how epithelial, mesenchymal, and vascular compartments are functionally integrated within the hair follicle niche to support cyclical regeneration [5].

2.1.2. Hair Cycle

The hair cycle consists mainly of anagen, catagen and telogen, followed by the shedding of the existing hair during exogen [22,23]. At the beginning of anagen, signals from the DP first activate the secondary hair germ and then stimulate bulge HFSCs [25]. Their progeny extends downward into the dermis and rebuild the lower part of the follicle around the DP [22,25]. Matrix cells then proliferate and differentiate to form the hair shaft and IRS [1,22]. Because hair production continues throughout anagen, the duration of this phase strongly influences final hair length [23].

During catagen, matrix-cell proliferation stops and the lower follicle undergoes rapid regression [22,23]. Many cells in the lower follicle are removed through apoptosis, while the DP moves upward with the regressing epithelial strand [1,32]. Transforming growth factor-beta 2 (TGF-β2) contributes to catagen induction in human hair follicles and promotes the transition away from active growth [33]. At the same time, the IRS begins to break down, and the remaining hair shaft develops into a club hair [22,23].

Telogen represents the rest phase of the hair cycle, during which the lower follicle has fully regressed, and epithelial proliferation is minimal [22]. In this stage, the DP is positioned directly below the secondary hair germ, allowing signaling between the mesenchymal and epithelial compartments to continue [1,25]. Telogen is not a completely inactive phase because changes in the local signaling environment determine when the follicle can re-enter anagen [34,35]. When activating signals become strong enough, the secondary hair germ responds first and initiates a new cycle of follicular growth [25].

2.1.3. The HFSC Niche in Hair Follicle Regeneration

HFSC behavior is regulated by a dynamic microenvironment composed of the DP, extracellular matrix, immune cells, adipose-lineage cells, sensory nerves and local vasculature [36,37]. The composition and signaling activity of this niche change throughout the hair cycle, collectively determining whether HFSCs remain quiescent or become activated to initiate follicular regeneration [34,37]. Rather than functioning as independent regulators, these niche components converge on signaling networks that coordinate stem cell activation with changes in the surrounding tissue (Figure 1).

Among these signaling pathways, Wnt/β-catenin and bone morphogenetic protein (BMP) signaling have central and opposing roles in regulating the balance between HFSC activation and quiescence [34,35]. In the absence of Wnt signaling, cytoplasmic β-catenin is phosphorylated by a destruction complex containing AXIN, APC, GSK3β and CK1 and subsequently targeted for degradation [28,38]. Wnt receptor activation inhibits this process, allowing β-catenin to accumulate in the nucleus and interact with TCF/LEF transcription factors to induce genes involved in follicular growth and regeneration [28,38]. β-Catenin activity within the DP is also required for normal follicular morphogenesis and regeneration, illustrating the importance of Wnt signaling in both epithelial and mesenchymal compartments [39]. DPC-derived biglycan can further promote hair-cycle progression and follicular regeneration through activation of Wnt/β-catenin signaling [40]. However, Wnt activity requires tight spatial and temporal control, as constitutive β-catenin activation in mouse skin can induce both ectopic hair follicle formation and hair tumors [41].

In contrast, BMP signaling contributes to the maintenance of HFSC quiescence and prevents premature entry into a new regenerative cycle [34,42]. High BMP activity characterizes the refractory stage of telogen, during which follicles are relatively unresponsive to growth-promoting signals [34]. As telogen progresses, declining BMP activity increases follicular competence to respond to activating signals, including Wnt [34,35]. The balance between BMP6 and Wnt10b represents one mechanism regulating the telogen-to-anagen transition [35]. Inhibition of BMP signaling shortens the refractory phase, whereas exogenous BMP4 can return competent regions of mouse skin to a refractory state [34,35]. Hair-cycle entry therefore reflects the dynamic balance between inhibitory and activating signals rather than the activity of either pathway in isolation.

Mesenchymal cells surrounding the follicle provide additional signals that modulate these core regenerative pathways. R-spondin produced within the follicular mesenchyme regulates dermal progenitor activity, while interactions between fibroblast growth factor (FGF) and Wnt signaling contribute to the timing of the murine hair cycle [43,44]. The broader HFSC niche extends beyond the DP and includes structural, neural, immune, and adipose components. Bulge HFSCs actively participate in establishing this niche by depositing the extracellular matrix protein nephronectin into the basement membrane [45]. Nephronectin binds α8β1 integrin on adjacent mesenchymal cells, promoting their differentiation into smooth muscle cells and directing the selective attachment of the arrector pili muscle to the bulge [45]. Sensory nerves adjacent to the upper bulge form a specialized perineural niche by providing Sonic hedgehog (SHH), which activates Hedgehog signaling in a distinct population of Gli1⁺ bulge stem cells [46]. These SHH-responsive cells contribute to long-term follicular maintenance and exhibit enhanced lineage plasticity during tissue repair [46]. Their responsiveness to SHH is facilitated by high expression of growth arrest specific 1 (GAS1), a Hedgehog co-receptor that enhances SHH signaling and promotes HFSC proliferation [47].

Immune and adipose-lineage cells provide additional regulatory signals [48,49]. Skin-resident regulatory T cells express high levels of the Notch ligand Jagged 1 (Jag1), which promotes HFSC activation and efficient follicular regeneration through Notch signaling [49]. Changes in dermal adipocyte precursor populations are similarly coordinated with HFSC activation, in part through platelet-derived growth factor (PDGF) signaling [48]. In human dermal adipose tissue, hepatocyte growth factor has also been shown to promote hair growth and pigmentation [50].

Importantly, communication within the HFSC niche is bidirectional, as HFSCs and their progeny can contribute to the signals that regulate a subsequent regenerative cycle [51,52]. Early HFSC descendants can retain stem cell characteristics and slow-cycling capacity and subsequently return to the bulge after the growth phase [52]. Even more differentiated descendants can re-enter the bulge and contribute regulatory signals to the local niche [52]. Returning progeny express factors including FGF18 and BMP6, which help re-establish HFSC quiescence and organize the subsequent regenerative cycle [52]. The niche is therefore not a fixed anatomical compartment surrounding a stable stem cell population, but a dynamically reconstructed signaling environment in which HFSCs, their progeny, and surrounding stromal cells reciprocally regulate one another.

HFSCs are not only regulated by the surrounding niche but can also organize vascular, lymphatic and mesenchymal components of the skin [53]. In mouse skin, altered epithelial expression of Runx1, a transcription factor involved in HFSC regulation, changed the arrangement of blood vessels around the hair germ [54]. Similarly, endothelial deletion of Alk1, a receptor involved in vascular homeostasis, increased local vascular density and delayed HFSC activation and entry into anagen [54]. These findings show bidirectional communication between HFSCs and the vasculature that coordinates stem cell activity with vascular remodeling [54]. Similar interactions with perifollicular lymphatic vessels further support a role of HFSCs in organizing their local microenvironment [55,56].

The importance of this microenvironment becomes particularly apparent when the niche is altered by aging. Transplantation experiments have shown that aged HFSCs regain substantial regenerative capacity when placed in young dermis, whereas young HFSCs exhibit impaired regeneration within an aged dermal environment [57]. Aging is also associated with reduced proximity and reciprocal signaling between ECs and the DP, leading to impaired angiogenic activity and hair regeneration [5]. Although these observations derive primarily from mouse and aging models rather than human AGA, they provide an important conceptual framework for understanding how alterations in inflammation, extracellular matrix composition, fibrosis and vascular function could impair follicular regeneration in AGA [8,12].

2.2. Vascular Regulation and Dysfunction in AGA

The hair follicle is surrounded by a perifollicular capillary network that is closely associated with the DP and provides oxygen and nutrients required to support follicular growth and regeneration [5,54]. This network undergoes coordinated remodeling throughout the hair cycle, with increased vascularization during anagen followed by vascular regression during catagen and telogen [3,54]. The close temporal relationship between angiogenesis and follicular growth suggests that vascular remodeling is coordinated with changes in the metabolic and regenerative demands of the follicle.

VEGF is a major mediator of this hair-cycle-associated angiogenesis [3,29,37]. Within the follicle, VEGF is expressed by follicular keratinocytes, particularly those of the ORS, and has also been detected in DPCs and ECs [3,29]. Follicular VEGF expression increases during anagen and declines during telogen, consistent with the cyclical remodeling of the perifollicular vasculature [3]. Experimental manipulation of VEGF provides evidence that these vascular changes can influence follicular growth. In transgenic mice, VEGF overexpression increased perifollicular vascularization and accelerated hair growth, whereas VEGF neutralization reduced vascularization, retarded hair growth and decreased follicular size [3]. VEGF has also been reported to promote proliferation of DPCs in vitro, suggesting that its effects may extend beyond angiogenesis to direct regulation of follicular cells [58]. Together, these findings identify VEGF as an important molecular link between follicular activity and perifollicular vascular remodeling.

The functional importance of an adequate vascular supply is further supported by experimental manipulation of tissue perfusion. Increased oxygen availability can support follicular morphology and cellular proliferation, whereas vascular insufficiency impairs these processes [4]. In ischemic skin-flap models, reduced perfusion delayed hair growth and produced changes including decreased hair-shaft diameter and hair density [4]. Therefore, impaired tissue perfusion is sufficient to compromise normal hair growth and provide biological plausibility for a contribution of vascular dysfunction to disorders of follicular regeneration.

The perifollicular vascular niche around the hair follicle also includes lymphatic vessels [55,56]. In mouse skin, these vessels are mainly located around the permanent upper region of the follicle and connect nearby follicles at the bulge level [55]. Lymphatic vessels undergo dynamic remodeling during HFSC activation and hair regeneration [55,56]. Following HFSC activation, a switch from angiopoietin-like protein 7 (ANGPTL7) to ANGPTL4 promotes transient separation of lymphatic vessels from HFSCs and reduces local drainage [56]. Disruption of this signaling switch led to premature anagen entry and impaired coordination of hair cycling, whereas depletion of lymphatic vessels blocked hair follicle growth, highlighting lymphatic remodeling as an important component of the HFSC niche during hair regeneration [55,56].

Despite the close physiological relationship between perifollicular vascular remodeling and hair growth, direct evidence for vascular dysfunction in AGA remains limited. An early clinical study reported significantly lower subcutaneous scalp blood flowing in men with early male pattern baldness than in age-matched controls [16]. A separate study found lower oxygen partial pressure in the balding frontal scalp than in hair-bearing temporal scalp and in corresponding scalp regions of control subjects [17]. These findings are consistent with reduced perfusion and oxygen availability in affected AGA scalp. However, they did not establish whether reduced perfusion precedes follicular miniaturization or develops secondarily as follicular activity and metabolic demand decline. Thus, while experimental studies demonstrate that vascular insufficiency can impair hair growth, whether vascular dysfunction is a causal driver of human AGA remains unresolved.

2.3. Inflammation, Fibrosis, and Tissue Remodeling in AGA

Although AGA is primarily considered an androgen-dependent, non-scarring form of hair loss, histological and molecular evidence indicates that affected follicles also exist within an altered immune microenvironment [13,15,59]. Histological studies of AGA scalp have identified perifollicular inflammatory infiltrates, particularly around the infundibular and isthmic regions of affected hair follicles, consisting predominantly of T lymphocytes and macrophages [13,15]. Increased numbers of mast cells and perifollicular collagen deposition have also been reported, suggesting that low-grade inflammation can coexist with local tissue remodeling [15]. Since this inflammatory response is generally mild and does not produce the irreversible follicular destruction characteristic of cicatricial alopecia, it is commonly described as perifollicular microinflammation [8,12].

Recent transcriptomic and spatial studies have provided further evidence of immune dysregulation in AGA [59,60,61]. Spatial transcriptomic analysis identified altered immune activity surrounding affected follicles, particularly within the upper follicular regions where histological inflammatory infiltrates have also been observed [59]. Transcriptomic profiling of AGA scalp similarly revealed changes in immune cell infiltration together with altered expression of genes involved in inflammatory responses and extracellular matrix organization [60]. More recently, integrated single-nucleus and bulk RNA sequencing identified enrichment of natural killer cells and CD8⁺ T cells in balding follicles and stronger inflammatory signatures in more advanced AGA [61]. Notably, this study also reported reduced expression of angiogenesis-related genes in blood ECs and increased IL-15 expression across several follicular cell populations, raising the possibility that immune and vascular alterations are interconnected components of the AGA microenvironment [61]. However, these molecular studies are largely observational and do not establish whether immune dysregulation precedes follicular miniaturization or develops as a consequence of progressive follicular remodeling [59,61].

Androgen receptor (AR) signaling may provide one mechanism through which the primary hormonal driver of AGA contributes to broader changes in the follicular microenvironment [62,63,64,65]. In androgen-sensitive DPCs, DHT activates AR-dependent transcription and alters the production of paracrine factors that regulate surrounding follicular cells [8,65]. DHT can alter the production of growth-inhibitory and inflammatory factors in DPCs [62,64]. DHT-induced IL-6 can inhibit matrix cell proliferation and hair shaft elongation [62]. DHT can also induce oxidative stress and cellular senescence in DPCs [64]. Functional evidence supports a role for at least some of these factors in suppressing hair growth. DHT increases IL-6 secretion from balding DPCs, while recombinant IL-6 inhibits matrix cell proliferation and hair shaft elongation in cultured human hair follicles [62]. Administration of IL-6 during anagen also induces premature catagen in mice [62]. Androgen signaling may additionally impair the regenerative function of the mesenchymal niche through mechanisms beyond inflammation. In cultured DPC spheroids, androgen treatment reduced BMP2 and BMP4 expression, whereas BMP2 supplementation restored DPC inductive activity and promoted HFSC differentiation [63]. DHT has also been shown to induce DPC senescence through p38-dependent alterations in endoplasmic reticulum-mitochondrial interactions, linking androgen signaling to cellular stress and loss of regenerative function [64]. Thus, androgen-responsive DPCs may contribute to microenvironmental remodeling through altered cytokine production, oxidative stress, senescence, and epithelial-mesenchymal signaling.

Such changes in the follicular niche may be particularly relevant because follicular miniaturization in AGA occurs despite persistence of the HFSC reservoir. Analysis of matched balding and non-balding scalp from men with AGA demonstrated that HFSCs were retained in balding follicles, whereas progenitor cell populations required for follicular regeneration were markedly reduced [7,66]. This finding suggests that impaired regeneration may involve defective activation or differentiation of quiescent HFSCs into progenitor populations rather than depletion of HFSC themselves. Since these progenitor cells contribute to the formation of the new lower follicle at anagen onset, their reduction may limit follicular regeneration and the production of a normal terminal hair [7,66]. The persistence of HFSCs in AGA follicles also raises the possibility that impaired follicular regeneration may be partially reversible. Consistent with this concept, local administration of autologous hair follicle-derived mesenchymal stem cells increased the proportion of terminal hairs and hair shaft diameter in patients with AGA, though the improvements gradually declined after several months [67]. Taken together, the chronic inflammation around the upper follicle and the reduction of progenitor cell population raise the possibility that local inflammation may interfere with stem cell activation and progenitor cell formation in AGA [14,66]. However, a direct causal relationship between these two changes has not yet been demonstrated [14,66].

In addition to altering cellular signaling within the follicular niche, chronic low-grade inflammation may be associated with structural remodeling of the surrounding extracellular matrix. Histopathological analysis has identified perifollicular fibrosis together with abnormal extracellular matrix organization, such as increased collagen deposition and altered distribution of elastin across different dermal layers in AGA scalp [2], particularly around the lower infundibulum and isthmus of affected hair follicles [15]. Mast cells accumulate in areas of perifollicular fibrosis and may contribute to local extracellular matrix remodeling through the release of profibrotic mediators [8,12]. TGF-β represents one potential link between androgen signaling and this fibrosis response [8,12]. Androgen-responsive DPCs can increase TGF-β1 production, while TGF-β1 promotes procollagen synthesis by scalp fibroblasts and may thereby contribute to perifollicular collagen accumulation [8,12]. Persistent extracellular matrix remodeling could alter the mechanical and biochemical properties of the follicular niche and potentially interfere with the epithelial-mesenchymal interactions required for normal regeneration. However, the available evidence does not establish whether perifollicular fibrosis actively contributes to follicular miniaturization or develops primarily as a secondary consequence of chronic follicular degeneration.

2.4. Crosstalk Between Inflammation and Vasculature

The findings discussed above suggest that inflammatory, fibrotic and vascular alterations in AGA may be interconnected rather than independent features of follicular remodeling (Figure 2). Androgen-responsive DPCs may represent an important point of convergence within this network. In particular, TGF-β signaling provides a potential mechanistic link, as androgen-induced changes in DPC paracrine signaling may simultaneously promote endothelial dysfunction and extracellular matrix remodeling [8,12,68]. The observation of microvascular regression within miniaturizing follicles further suggests that vascular alterations can occur during the process of follicular miniaturization rather than solely as a late consequence of hair loss [68].

3. Therapeutic Implications

3.1. Current Therapeutic Landscape and Unmet Needs

Current pharmacological treatment for AGA is mainly based on reducing androgen signaling or promoting hair growth, with oral finasteride and topical minoxidil remaining the principal FDA-approved medications for male AGA [69]. Other approaches, including topical finasteride, low-dose oral minoxidil, spironolactone and platelet-rich plasma (PRP), are increasingly used or investigated as off-label or adjunctive treatments [70,71,72,73]. Although these therapies act through different mechanisms, their effects are generally incomplete and do not comprehensively address the inflammatory, vascular and extracellular matrix abnormalities associated with the follicular microenvironment in AGA [12,69].

Finasteride targets the central androgen-dependent mechanism of AGA by inhibiting type II 5α-reductase, thereby reducing the conversion of testosterone into DHT and lowering DHT levels in both the serum and scalp [11]. Oral finasteride reduces hair loss and promotes hair regrowth, though continued treatment is generally required to maintain its therapeutic benefit [10,69,74]. Sexual adverse effects, including reduced libido and erectile or ejaculatory dysfunction, have been reported, though their frequency and persistence vary among studies [75].

Topical finasteride has therefore been developed to reduce scalp DHT while limiting systemic exposure [70]. In a phase III randomized trial, topical finasteride significantly increased hair count compared with placebo and produced an effect numerically similar to oral finasteride, while resulting in substantially lower plasma drug exposure and serum DHT suppression [70]. Nevertheless, systemic absorption was not completely eliminated. Thus, topical delivery may reduce systemic exposure while retaining local anti-androgen activity [70].

Minoxidil promotes hair growth through mechanisms that extend beyond its vasodilatory activity and may include modulation of follicular vascular support and communication between DPCs and ECs [29]. However, the contribution of vascular remodeling to its clinical efficacy in AGA remains incompletely defined [76,77,78,79]. Although topical minoxidil is effective, the requirement for regular application and local adverse effects such as scalp irritation can limit long-term adherence [80]. Low-dose oral minoxidil has consequently emerged as an alternative, particularly for patients who cannot tolerate or consistently use topical formulations [71,77]. Randomized and comparative studies suggest that oral and topical minoxidil generally produce comparable improvements in hair growth, though oral minoxidil may provide greater improvement in some scalp regions [76,77]. Low-dose oral minoxidil is generally well tolerated, with hypertrichosis being the most common adverse effect and systemic events such as light-headedness, fluid retention and tachycardia occurring less frequently [71,77]. Larger randomized studies with extended follow-up are required to establish its long-term cardiovascular safety [71].

Given that minoxidil and anti-androgen treatments target distinct aspects of AGA pathophysiology, combination therapy may provide complementary therapeutic effects [72]. In women with AGA, topical minoxidil combined with either oral spironolactone or oral finasteride improved hair density, thickness and hair loss, with the spironolactone combination showing greater improvement in several later assessments [72]. These findings support combination therapy as a potential strategy for selected patients, although optimal treatment regimens and patient populations remain to be established.

PRP has also been studied as a regenerative treatment for AGA, but its clinical results remain inconsistent [73,81]. Qu et al. showed that PRP accelerated hair-cycle progression and promoted hair regrowth beyond one hair cycle in AGA mouse model through pathways including β-catenin activation and reduced p53-related signaling [73]. Clinical studies have reported improvements in hair count, density, and diameter, whereas a randomized split-scalp trial found no significant difference between PRP and saline-treated areas despite improvement from baseline [73,81]. These discrepancies may partly reflect differences in treatment protocols and potential effects of injection-associated microinjury or local diffusion. Moreover, mechanisms identified in experimental models cannot be assumed to operate similarly in human AGA.

Overall, currently available treatments may slow hair loss and produce partial hair regrowth in patients with AGA, but treatment responses remain variable and generally depend on continued therapy [70,74,77]. Their long-term utility may also be limited by adverse effects, treatment burden, or incomplete efficacy [71,75,80]. Importantly, established therapies predominantly target androgen signaling or stimulate follicular growth rather than simultaneously addressing the inflammatory, fibrotic and vascular alterations associated with follicular miniaturization [12,61,69]. These limitations support the development of more durable, practical, and mechanistically integrated strategies that target multiple interacting components of the AGA microenvironment [82,83,84].

3.2. Vasoactive Therapeutic Agents

Vascular modulation has emerged as a potential therapeutic strategy for AGA because the perifollicular vasculature provides metabolic support and regulatory signals required for hair follicle growth [5,29]. Single-nucleus RNA sequencing of human AGA follicles identified reduced expression of angiogenesis-related genes in blood ECs from balding compared with non-balding regions, supporting the presence of vascular alterations in human AGA [61]. However, these cross-sectional data cannot determine whether vascular dysfunction contributes to follicular miniaturization or develops as a consequence of it [61].

Minoxidil provides the strongest clinical precedent for a treatment with potential vascular effects, though its hair growth effect cannot be attributed solely to vasodilation [78,79]. In addition to activating growth-associated pathways in DPCs, minoxidil may affect the communication between DPCs and ECs through VEGF-related and CCL2-related signaling [29]. Minoxidil increased perifollicular vascularization in mice, while EC-derived signals induced CCL2 expression in DPCs, which in turn promoted EC proliferation and tube formation [29]. Inhibition of CCL2 attenuated the vascular response to minoxidil [29]. These findings suggest that minoxidil may modulate reciprocal signaling between DPCs and ECs rather than simply increasing blood flow. However, clinical trials have primarily assessed hair growth outcomes rather than perifollicular vascular function, and the contribution of vascular remodeling to the clinical efficacy of minoxidil remains uncertain [76,77].

More direct vascular-targeting strategies have therefore been explored in preclinical models. Local delivery of VEGF using a hydrogel-forming microneedle system increased perifollicular angiogenesis and promoted anagen entry and hair regrowth in an AGA mouse model [82]. However, VEGF was delivered together with the JAK inhibitor ritlecitinib and microneedle-based stimulation, making the independent contribution of angiogenesis difficult to determine [82]. Moreover, increased angiogenic activity does not necessarily indicate the formation of a mature and functionally perfused vascular network [82]

Nitric oxide (NO) has also been investigated because of its effects on vasodilation, endothelial function and inflammation. Several local delivery platforms combining NO donors with minoxidil have enhanced angiogenic activity and hair regeneration in experimental AGA models [83,85,86]. Controlled systems, including near-infrared (NIR) responsive hydrogels and microneedles, may enable localized NO release while limiting systemic exposure [85,86]. Nevertheless, since NO has generally been administered together with minoxidil or specialized delivery systems, its independent contribution to hair regeneration remains unclear.

More complex combination approaches aim to simultaneously target vascular dysfunction and other components of the AGA microenvironment [84]. For example, a dissolvable microneedle system combining NO-generating Weissella cibaria with the androgen receptor antagonist clascoterone enhanced vascular regeneration, reduced perifollicular inflammation, and promoted hair growth in an AGA mouse model [84]. This strategy illustrates the potential value of simultaneously modulating vascular, inflammatory, and androgen-dependent pathways, although its complexity will require careful evaluation of the contribution, safety, and translational feasibility of individual components [84].

Beyond pharmacological approaches, tissue-engineering studies further support a functional interaction between DPCs and vascular ECs. DPCs cultured as three-dimensional spheroids exhibited increased expression of angiogenic factors and enhanced EC migration and tube formation compared with conventional monolayer cultures [87]. Similarly, incorporation of vascular ECs into engineered hair follicle germs enhanced follicular regenerative capacity and hair formation after transplantation in mice [88]. Therefore, therapies that preserve or restore DPC-EC communication may provide broader benefits than treatments that only increase local blood flow, although this possibility still requires validation in human AGA [30].

Drug-delivery strategies may also enhance local vascular effects of established therapies. Mesenchymal stem cell membrane-coated minoxidil nanoparticles increase cutaneous drug retention, hair growth, and expression of angiogenesis-associated factors in experimental models [89]. However, increased VEGF expression or other angiogenic markers alone does not demonstrate restoration of a mature and functional perifollicular vascular network [89].

Overall, vascular modulation represents a promising but predominantly preclinical strategy for AGA. Current studies largely rely on surrogate measures such as VEGF expression, endothelial tube formation and CD31 staining, which indicate angiogenic activity but do not establish restoration of stable and functionally perfused vessels [82,83,84,85,86,87]. Future studies should directly assess perifollicular perfusion, oxygen delivery and vessel stability and determine whether vascular-targeted interventions provide additional benefit beyond established AGA therapies [61,76,77,82]. Importantly, since vascular dysfunction occurs alongside inflammatory, fibrotic, and androgen-dependent alterations, vascular restoration may ultimately be most effective as one component of a broader microenvironment-directed therapeutic strategy.

3.3. Anti-Inflammatory and Anti-Oxidative Stress Therapeutic Agents

Inflammatory mediators and prostaglandins may contribute to the hair cycle dysregulation and alterations of the perifollicular microenvironment in AGA [90]. Cetirizine, a second-generation histamine H1-receptor antagonist with anti-inflammatory properties, has been proposed to promote hair growth by reducing the inhibitory effects of prostaglandin D2 (PGD2) and favoring prostaglandin E2 (PGE2)-associated signaling [90,91]. Clinical studies of topical cetirizine have reported improvements in hair growth, though its efficacy appears lower than that of topical minoxidil [90]. However, these studies assessed hair growth outcomes without directly measuring prostaglandin levels, inflammatory mediators, or immune cell activity. Thus, although cetirizine may provide a potential approach to modulating the inflammatory microenvironment in AGA, the mechanisms underlying its clinical effects remain to be established [90,91].

Excessive reactive oxygen species (ROS) may disrupt the perifollicular microenvironment by impairing local vasculature and limiting HFSC activation [92,93]. Nanozyme-based microneedle systems have therefore been explored as a strategy to reduce oxidative stress while improving local delivery to miniaturized hair follicles [92,93,94].

Early approaches focused primarily on restoring redox homeostasis. Ceria nanozymes incorporated into dissolving microneedles represent an early example of this approach [92]. Through their catalase- and superoxide dismutase-like activities, ceria nanozymes reduced excessive ROS, while microneedle treatment also promoted local microvascular remodelling [92]. Similarly, a related strategy employed platinum nanozymes delivered by dissolving microneedles [93]. In addition to reducing oxidative stress, platinum nanozymes promoted local oxygen generation, which was associated with improved cellular energy metabolism and HFSC progression [93]. This treatment also enhanced hair regeneration in a preclinical AGA model, supporting the potential of nanozyme-based modulation of the perifollicular redox and metabolic environment [93].

More recently, a multifunctional microneedle system combining hypoxia-conditioned extracellular vesicles with selenium nanoparticles was developed to target several components of the AGA microenvironment simultaneously [94]. In AGA mice, treatment increased hair density and follicle diameter and was associated with reduced oxidative stress and inflammation, enhanced angiogenesis, and protection against androgen-related injury [94]. Compared with strategies focused primarily on ROS removal, this approach illustrates the potential value of simultaneously targeting multiple abnormalities within the perifollicular microenvironment [94].

Overall, nanozyme-based microneedle systems offer a promising approach to modulating oxidative stress and other features of the AGA microenvironment while facilitating local delivery [92,93,94]. However, their efficacy, safety, tissue retention, and comparative benefit over established AGA treatments in humans remain to be determined [92,93,94].

3.4. Emerging Delivery and Microenvironment-Modulating Strategies

Emerging delivery systems may improve AGA treatment by enhancing drug accumulation within and around hair follicles while limiting off-target tissue exposure [89,95,96]. Beyond improving drug delivery, multifunctional platforms can simultaneously modulate components of the follicular microenvironment, including angiogenesis, inflammation and oxidative stress [83,94,97]. Such integrated approaches may be particularly valuable because enhanced drug penetration alone does not address the multiple microenvironmental abnormalities associated with follicular miniaturization [5,61]. However, most of these strategies remain at the preclinical stage, and further studies are required to determine whether their microenvironmental effects translate into durable and functional follicular regeneration in patients with AGA (Figure 3).

3.4.1. Ultrasound-Assisted Therapy

Low-intensity ultrasound has been investigated as a physical approach to enhance the local pharmacological activity of finasteride [98]. In a murine model of androgen-related hair loss, ultrasound combined with oral finasteride enhanced hair regeneration compared with finasteride alone, as reflected by increased follicle number and size and a greater proportion of follicles in anagen [98]. The absence of detectable tissue heating suggested that these effects were unlikely to result primarily from a thermal mechanism [98].

Ultrasound may increase local finasteride availability by altering its interaction with albumin [98]. However, unbound finasteride and tissue drug concentrations were not directly measured, and changes in local perfusion or vascular permeability were not assessed. Thus, although ultrasound enhanced the local therapeutic effect of finasteride, the mechanisms underlying this enhancement remain unclear. Further studies incorporating local pharmacokinetic and vascular measurements are needed to determine whether ultrasound improves drug availability or modifies drug exchange within the perifollicular microenvironment [61,98].

3.4.2. Mechanical Modulation of the HFSC Niche

Mechanical signaling within the follicular niche may represent another potential target for regenerative therapy [99]. In mouse hair follicles, PIEZO1 was highly expressed in quiescent bulge HFSCs, where mechanical stimulation induced PIEZO1-dependent calcium signaling [99]. PIEZO1 is a mechanically activated ion channel that converts physical forces in the local tissue environment into intracellular calcium signals [99]. This pathway promoted the activity of NFATC1 and AP-1 and maintained transcriptional programs associated with extracellular matrix organization, cell adhesion and cytoskeleton regulation, linking mechanical sensing to HFSC quiescence and niche homeostasis [99].

Loss of PIEZO1 reduced calcium signaling and bulge stiffness while shortening telogen and accelerating hair cycle, suggesting that modulation of mechanosensing can alter the balance between HFSC quiescence and activation [99]. However, genetic deletion of PIEZO1 does not represent a directly translatable therapeutic strategy, and these findings have not been established in human AGA [99]. Moreover, excessive or sustained disruption of HFSC quiescence could potentially compromise long-term stem cell maintenance. Future studies should therefore determine whether localized and reversible modulation of mechanical signaling can promote follicular regeneration while preserving stem cell function and tissue integrity [99].

3.4.3. Transferable Strategies from Vascularized Skin Repair

Therapies developed for skin wounds may offer useful ideas because wound repair also requires controlled inflammation and angiogenesis. In murine impaired wounds, dissolving GelMA microneedles carrying recombinant human proteoglycan 4 reduced TNF-α and IL-6 and increased angiogenesis and collagen deposition [100]. An extracellular-matrix-mimetic glycopeptide hydrogel promoted M2-like macrophage activity and angiogenesis in infected diabetic and burn wounds without added cells or cytokines [101]. These studies show that a local material can coordinate immune and vascular responses [100,101].

A PDGF-BB-mimetic supramolecular hydrogel also promoted endothelial growth and vessel branching in vitro and increased early CD31-positive neovascularization in mouse wounds [102]. Such materials could be adapted to deliver signals around miniaturized follicles [102]. However, wound angiogenesis is temporary and occurs in damaged tissue, whereas AGA requires long-term support of a cycling follicle. Before translation, these systems should be tested in AGA models for vessel perfusion, fibrosis and repeated-dose safety.

3.4.4. Hydrogel-Based Delivery Systems

Hydrogel-based delivery systems have also been explored to improve local drug retention and modulate the follicular microenvironment. A sodium alginate hydrogel providing sustained release of 2-deoxy-D-ribose was evaluated in a testosterone-induced AGA mouse model [103]. Treatment promoted hair regrowth with effects approaching those of topical minoxidil and was associated with increased local vascularization. However, combining 2-deoxy-D-ribose with minoxidil provided no significant additional benefit [103].

A more multifunctional approach combined minoxidil-loaded liposomes with an injectable bioactive hydrogel. The system was designed to improve minoxidil stability, retention and controlled release while providing additional antioxidant, antibacterial and microenvironment-modulating properties [104]. In preclinical models, the formulation promoted follicular development and hair regrowth more effectively than conventional topical minoxidil, while the drug-free hydrogel itself also showed some beneficial activity [104]. However, the formulation contains multiple functional components whose individual therapeutic contributions have not been fully resolved, and its efficacy and safety remain to be established in patients with AGA [104].

3.4.5. Nano-Enabled and Follicle-Targeted Delivery

Nano-enabled carriers can improve drug stability, overcome skin-delivery barriers and enhance accumulation within hair follicles [95]. A polyethylene glycol-modified black phosphorus nanosheet system was developed for topical delivery of metformin in AGA [95]. The formulation improved metformin stability and local delivery while providing additional antioxidant activity [95]. In preclinical models, treatment promoted anagen entry and hair regeneration with reduced local adverse effects, though the long-term safety of black phosphorus-based materials remains to be established [95].

Beyond drug encapsulation, the physical properties of nanocarriers may influence follicular targeting [96]. A fucosterol-loaded nanopore system demonstrated that increasing carrier rigidity enhanced follicular accumulation and hair regeneration in a preclinical AGA model [96]. Treatment was also associated with reduced inflammatory and androgen-related signaling and enhanced angiogenesis [96]. These findings identify carrier rigidity as a potentially important parameter for optimizing follicle-targeted drug delivery [96].

Nano-enabled delivery has also been combined with microneedle technology to target multiple features of the follicular microenvironment. A dissolving microneedle system containing liposomal ginsenoside compound K with a nitric oxide donor enhanced local delivery and promoted hair regeneration in a preclinical AGA model [97]. These effects were associated with increased cellular proliferation and angiogenesis together with modulation of inflammatory activity [97]. The approach illustrates the potential of combining follicle-targeted delivery with simultaneous regulation of the local microenvironment [97].

Overall, nano-enabled platforms may improve follicular drug delivery while incorporating additional antioxidant, angiogenic and anti-inflammatory functions. However, these increasingly complex formulations may introduce additional manufacturing and safety challenges, and their advantages over simpler delivery systems remain to be demonstrated clinically. Further pharmacokinetic, safety and controlled clinical studies are therefore required to establish their translational value in AGA.

4. Future Directions and Research Gaps

4.1. Unresolved Mechanistic Questions

An important unresolved question is how inflammation, vascular dysfunction and follicular miniaturization are temporally and causally related in AGA. Although inflammatory changes and impaired vascular support have been observed in affected scalp tissue, most available human studies are cross-sectional and therefore cannot determine which alterations occur first [13,15,59,61]. Reduced perfusion could contribute to follicular dysfunction by limiting metabolic and oxygen support, but it could also arise secondarily as miniaturized follicles become less metabolically active [4,16,17]. Similarly, inflammation may impair the vascular niche, whereas vascular insufficiency may itself promote tissue stress and inflammatory responses. These processes may therefore represent interacting components of a self-reinforcing microenvironment rather than independent abnormalities with a simple linear relationship.

Current experimental models provide limited opportunities to resolve these relationships. Depilation and androgen-induced mouse models are useful for evaluating hair regeneration but do not fully reproduce the gradual progression, asynchronous follicular cycling and chronic microenvironmental changes of human AGA [1,22,82,92,93]. It is also unknown whether lymphatic remodeling is altered in human AGA or related to follicular miniaturization [55,56]. Future studies should therefore place greater emphasis on longitudinal human samples and complementary human follicle and multicellular culture models [5,61,88]. Integrating temporal changes in vascular, immune and follicular compartments may help distinguish early drivers from secondary consequences and determine whether these processes form a continuing feedback loop during AGA progression.

4.2. Need for Improved Biomarkers

Clinical assessment of AGA relies largely on hair-loss patterns and quantitative measures of hair density and hair shaft diameter [6]. Although useful for assessing disease severity and treatment response, these measures provide little information about the underlying follicular microenvironment [6,15]. Patients with similar clinical presentations may therefore differ in the relative contributions of androgen signaling, inflammation, vascular dysfunction, fibrosis and impaired follicular regeneration [59,61].

Recent transcriptomic studies have identified potential biomarkers that may capture the biological heterogeneity. Spatial and single-cell analyses have revealed altered immune activity in affected follicles, including increased NK and CD8⁺ T cell activity and IL-15 expression in more advanced AGA [59,61]. Changes in extracellular matrix-related genes, including COL1A2, PCOLCE and LOX, have also been reported [60]. Although these findings provide potential molecular indicators of immune and ECM alterations, their association with disease progression and treatment response remains unclear.

Future clinical studies should therefore integrate conventional hair-growth outcomes with molecular and functional assessment of the follicular microenvironment. Candidate biomarkers could incorporate measures of immune activity, extracellular matrix remodeling and vascular function with minimally invasive approaches being particularly valuable for longitudinal monitoring. Importantly, biomarkers should reflect biologically meaningful changes rather than isolated molecular signals. For example, increased angiogenic signalling does not necessarily indicate the formation of functional, perfused vessels [59,61]. Ultimately, clinically useful biomarkers should not only correlate with disease severity but also predict progression or response to specific treatments, potentially enabling biologically informed patient stratification and treatment selection.

4.3. Integration of Single-Cell and Spatial Transcriptomic Approaches

Single-cell and spatial approaches provide an opportunity to resolve the cellular and anatomical complexity of the follicular microenvironment. Spatial transcriptomics can localize molecular alterations within affected scalp tissue, while single-cell and single-nucleus sequencing can identify the cell populations associated with these changes [59,61]. Their integration is particularly relevant to AGA, in which DPCs, ECs, mesenchymal and immune compartments may undergo distinct but interacting changes during follicular miniaturization [5,61].

Recent studies have demonstrated the potential of these approaches by revealing spatially restricted immune alterations, changes in vascular cell states and previously unresolved intercellular communication in affected follicles [59,61].

Importantly, integrated single cell and spatial analyses may also identify intercellular signaling pathways that contribute to AGA progression. Proposed interactions involving DPCs, ECs and immune cells, including CCL2, IL-15, EDN1-EDNRA and CTF1-IL6ST-related signaling, may connect cellular metabolism, angiogenesis and follicular regeneration [5,29,61]. However, some of these pathways were identified in aging or experimental hair-cycle models rather than human AGA and therefore require disease-specific validation [5,29]. Integrating transcriptomic observations with proteomic, metabolic and functional studies will be essential to distinguish causal regulatory pathways from secondary changes associated with follicular miniaturization [5,105].

4.4. Precision Medicine and Personalized Therapy

AGA is clinically and biologically heterogeneous, and patients with similar patterns of hair loss may differ in the mechanisms contributing to follicular miniaturization and treatment response [6,106]. This heterogeneity suggests that future treatment selection may benefit from biological information beyond conventional clinical classification.

A precision-medicine approach could potentially integrate androgen sensitivity with inflammatory, vascular and extracellular matrix features of the follicular microenvironment. Such information might eventually identify patients more likely to benefit from therapies targeting specific biological abnormalities, including inflammation, impaired vascular support or tissue remodeling [15,59,60,61]. However, these proposed biological subtypes remain hypothetical and should not guide clinical management until they are prospectively validated against disease progression and treatment response.

4.5. Combination Therapies Targeting Multiple Pathways

AGA arises from interactions among androgen signaling, impaired follicular regeneration and alterations in the surrounding microenvironment [7,8,12]. This multifactorial biology provides a rationale for therapeutic strategies that target complementary disease mechanisms rather than a single pathway. In particular, combining established treatments with approaches that modulate inflammation, oxidative stress or vascular support may potentially improve the magnitude or durability of hair regeneration.

Several preclinical systems have begun to explore this concept by simultaneously targeting vascular, inflammatory and androgen-related pathways [82,83,84,86]. These approaches include combinations of conventional or targeted drugs with angiogenic or NO-based interventions delivered through advanced local delivery systems. Although encouraging effects have been reported in experimental AGA models, current evidence does not establish whether multi-pathway approaches provide clinically meaningful advantages over simpler treatments.

Increasing therapeutic complexity may itself create important translational challenges. Multifunctional platforms often combine active drugs with carriers, biomaterials and other biologically active components, making it difficult to determine the contribution of each element to the observed effect [82,84,104]. Greater complexity may also increase manufacturing requirements, cost and potential safety concerns [95,96,104]. Future studies should therefore distinguish the effects of individual components and determine whether each added function provides sufficient therapeutic benefit to justify the additional complexity. Ultimately, promising combination strategies should be compared directly with established AGA treatments in controlled clinical trials incorporating both conventional hair growth outcomes and mechanistic biomarkers [61,76,77].

5. Conclusions

AGA is characterized by genetically influenced susceptibility to androgen-dependent follicular miniaturization, but increasing evidence suggests that this process occurs within a dynamically altered follicular microenvironment [7,8,12]. Changes in inflammatory activity, extracellular matrix organization and vascular support may interact with intrinsic follicular abnormalities and influence disease progression [15,60,61]. However, whether these microenvironmental changes initiate or accelerate miniaturization, or arise partly as consequences of declining follicular activity, remains unresolved because current evidence is largely cross-sectional or preclinical [4,59,61].

This emerging view expands the therapeutic landscape beyond direct modulation of androgen signalling and hair growth. Strategies targeting vascular, inflammatory, oxidative and regenerative components of the follicular microenvironment have shown promise in experimental models, but their clinical relevance remains to be established. Future progress will require longitudinal studies, physiologically relevant models and validated biomarkers that link microenvironmental changes to disease progression and therapeutic response [59,61]. Ultimately, defining how DPCs, ECs, immune cells and HFSCs interact during follicular miniaturization may enable a more mechanistic classification of AGA and support the development of biologically informed, individualized treatment strategies [5,29,61].