In line with an increase in UV exposure, the incidence of hyperpigmentation disorders in the elderly has increased. Preventive measures, such as sunscreen, topical or oral vitamins and antioxidants, remain one of the main options. However, other options, such as topical metformin, may also serve as a therapeutic choice, as it is non-toxic to normal cells, including melanocytes, keratinocytes, or fibroblasts. The study by Lehraiki et al (17) enhanced the mechanistic understanding of the role of topical metformin in modulating pigmentation pathways, underscoring its potential as a therapeutic candidate for hyperpigmentation disorders. Metformin decreases melanin synthesis in melanoma cells and normal human melanocytes by reducing cAMP levels and inhibiting CREB phosphorylation, leading to the downregulation of MITF and other key melanogenic genes such as tyrosinase, TRP1 and DCT. These effects occur independently of the AMPK pathway (17).

Subsequent clinical observations have expanded this mechanistic foundation, investigating the significance of these pathways in the treatment of melasma. A previous preliminary clinical study evaluated the use of topical metformin in the treatment of melasma, outlining mechanistic pathways informed by earlier experimental research (14). The findings demonstrated that metformin reduced intracellular cAMP levels and CREB phosphorylation, thereby downregulating MITF, an essential regulator of melanogenesis. These cascades resulted in the decreased expression of critical melanogenic enzymes, including tyrosinase, TRP-1 and TRP-2. Metformin is suggested to impede the attachment of protein kinase C-β to melanosomes, consequently interfering with melanin production through an alternative signaling pathway. The observed clinical improvements in patients with melasma treated with topical metformin correspond with these pathways, underscoring its potential as a safe and mechanistically validated depigmenting agent (14).

The study by AboAlsoud et al (5) further developed this clinical perspective through a randomized controlled trial, confirming the significance of the cAMP-MITF axis in depigmentation. The authors provided evidence that metformin lowers intracellular cAMP levels, leading to the deactivation of CREB and the downregulation of MITF, a key regulator of melanogenesis. These cascades ultimately suppress the expression of melanogenic enzymes such as tyrosinase, TRP-1 and TRP-2. The observed clinical outcomes, particularly the notable decrease in MASI scores akin to that of the standard triple combination cream, underscore the therapeutic significance of these pathways. The mechanistic pathway was inferred from prior studies, and the trial reinforces the evidence supporting the role of topical metformin in inhibiting MITF-driven pigmentation (5).

Complementing these findings, Ali Mapar et al (23) provided additional clinical insights while also suggesting the involvement of the AMPK pathway. Referencing earlier preclinical findings, the authors of that study noted that metformin may reduce intracellular cAMP levels, thereby downregulating MITF, a central regulator of melanogenesis. Such a suppression is associated with lower expression levels of melanogenic enzymes, such as tyrosinase, TRP-1 and TRP-2. Additionally, metformin has been linked to the modulation of the AMPK pathway, which may contribute to its broader regulatory effect on melanin synthesis. While the clinical trial focused on efficacy outcomes measured through MASI scores, the trend of continued improvement over 12 weeks supports the relevance of these mechanistic insights and underscores the therapeutic promise of topical metformin in pigmentary disorder (23).

Metformin supports anticancer therapy by activating the liver kinase B1-AMPK pathway to inhibit gluconeogenesis in hepatocytes (24). This pathway inhibits mTOR and protein synthesis (25). Patients with cancer often have a p53 gene mutation, resulting in an unchecked cell cycle, even during hyperplasia, progressing to the dysplasia stage (26). A checkpoint exists between DNA synthesis and the mitotic phase to recognize and repair DNA damage (27). To assess the therapeutic potential of transdermal metformin-loaded cubic phases for melanoma treatment, Yu et al (21) found that the topical application of metformin in a cubic phase gel significantly enhanced skin permeability and exhibited strong antitumor effects. A summarized overview of the anticancer mechanisms of metformin is illustrated in Fig. 2, with a more detailed depiction of its potential direct and indirect effects as an anticancer agent illustrated in Fig. 3. The unique structure of the cubic phase system, with its thermodynamically stable and lipid-rich matrix, enabled deeper skin penetration and prolonged metformin release, resulting in significant tumor growth inhibition and improved apoptotic activity in vivo. In addition to enhanced transdermal distribution, metformin has been demonstrated to trigger various cell death pathways via p-21 and AMPK-independent processes, resulting in apoptosis and autophagy (21). These effects are mediated by the activation of the tumor suppressor p53 and downregulation of anti-apoptotic Bcl-2, indicating that metformin may exert significant anti-melanoma effects via different intracellular targets, independent of typical metabolic stress mechanisms (21).

In addition to these results, Mousa et al (20) demonstrated the therapeutic potential of transdermal metformin administration by using the ethosomal gel technique to treat skin cancer. Unlike cubic phases, the ethosomal formulation utilizes ethanol and isopropyl alcohol to destabilize the stratum corneum and increase vesicle fluidity, resulting in improved skin permeability, smaller vesicle size and greater metformin entrapment efficiency. In this model, the anticancer effect of metformin was predominantly due to AMPK activation, and the consequent suppression of the mTOR signaling pathway was a major regulator of cancer cell proliferation, stemness and survival. The combined evidence from both studies (20,21) demonstrates that distinct transdermal delivery platforms, whether through cubic phases or ethosomes, not only optimize the skin absorption of metformin, but also enable it to act through complementary molecular pathways, rendering these systems promising non-invasive strategies for the management of melanoma and other skin cancers (20).

Long-term exposure to the sun is the most common cause of photoaging, where the mutual interplay between autophagy, oxidative stress and apoptosis is implicated (28). In combating photoaging, pharmacological and natural ingredients that modulate autophagy are currently gaining more attention. Among these emerging agents, metformin has shown promising anti-photoaging properties (29). The general pathways through which metformin prevents photoaging are briefly summarized in Fig. 2. Metformin exerts anti-inflammatory and cytoprotective effects against UVB-induced skin injury in keratinocytes and mice. UVB irradiation typically induces inflammation and cell death by increasing the secretion of cytokines such as IL-1β, TNF-α and fibroblast growth factor-2. Metformin treatment significantly reduced the expression of these inflammatory markers at both the transcriptional and protein levels, partly by inhibiting the nuclear translocation of C/EBPβ, a transcription factor responsible for IL-1β production, leading to an anti-inflammatory effect (15). Metformin therapy preserved epidermal architecture, minimized keratinocyte apoptosis and significantly reduced the IL-1β and TNF-α, both at the transcript and protein levels, according to the study by Xiao et al (15). Additionally, metformin protected keratinocytes from UVB-induced cell death, not only by blocking direct damage but also by reducing deleterious paracrine factors. The topical application of 0.6% metformin cream in mice mitigated UVB-induced skin damage, decreased inflammatory cell infiltration and improved tissue histology, suggesting the potential of metformin as a topical agent for photoprotection and treatment of UV-induced skin damage. Metformin decreased UVB-induced inflammatory signaling and oxidative damage by modifying this upstream regulatory mechanism, indicating its potential as a prophylactic medication against photo-induced skin injury (15).

These tissue-level protective benefits are confirmed by in vitro evidence of the capacity of metformin to reduce UVA-induced oxidative stress in dermal fibroblasts. Cui et al (19), in a comparable in vitro model, demonstrated that metformin effectively reduced UVA-induced oxidative stress in human skin cells. The reactive oxygen species (ROS) content in the UVA group was considerably higher (P#x003C;0.05) than that in the control group. However, the ROS content in the UVA + metformin group was lower (P#x003C;0.05) than that in the UVA group (19). According to these findings, topical metformin may exert a preventive effect against photoaging by increasing COL-1 synthesis and reducing intracellular ROS synthesis. The therapy reduced ROS levels and downregulated MMP-1 and MMP-3, enzymes involved in the degradation of the dermal extracellular matrix. At the same time, metformin increased the expression of COL-I, a critical structural component of the skin. These molecular alterations indicate that metformin not only shields cells from oxidative stress, but also promotes matrix preservation and regeneration, supporting its position as a potential anti-photoaging agent across both in vitro and in vivo settings (19).

Topical metformin exerts a comprehensive preventive effect against skin aging, including enhanced protection against UVA-induced photoaging. The study by Mostafa et al (4) using a mouse model investigated the potential of repurposing metformin to combat UVA-induced photoaging by modulating autophagy, oxidative stress, and apoptosis in the skin (4). That study revealed that topical treatment with 10% metformin significantly improved skin elasticity and histological structure, reduced oxidative stress (as indicated by decreased MDA and increased GSH levels), reduced inflammation (decreased IL-6), and suppressed collagen breakdown (reduced MMP-1) (4). The enhancement was linked to an increase in autophagic flux by upregulating cathepsin D and modulating LC3-II and p62 levels, thereby reversing the blockade of UVA-induced autophagy. In addition, metformin diminished apoptosis and restored antioxidant capacity, partly through the activation of nuclear factor erythroid 2 (Nrf-2). The benefits were further boosted when paired with coenzyme Q10 (CoQ10), indicating a synergistic interaction. CoQ10 amplified the protective effects of metformin, particularly in keratinocytes, supporting its combined use as a promising therapeutic strategy against photoaging. Furthermore, the activation of AMPK and the inhibition of the mTOR pathway were recognized as pivotal biochemical processes supporting metformin's protective effects. The use of ethosomal gel formulation enabled efficient skin penetration and sustained drug release, supported by ethanol and isopropyl alcohol, which improved vesicle stability and metformin encapsulation (4).

Topical application of metformin could shorten the duration of wound healing by inhibiting several inflammatory pathways, as summarized in Fig. 2. The two main inflammatory mechanisms blocked by topical metformin are the AMPK and NF-κB pathways (Fig. 4). This effect was reported by Zhao et al (30), who found that the chronic local application of metformin led to the increased expression of p-AMPK and its downstream target phosphorylated acetyl-CoA carboxylase, both of which are central to the AMPK signaling cascade. This molecular activation was closely associated with improved angiogenesis, as evidenced by increased CD31⁺ endothelial structures and enhanced collagen deposition in the wound beds. These effects were particularly pronounced in aged skin, where metformin effectively reversed age-related AMPK suppression and vascular deficiencies, ultimately accelerating wound closure and restoring cutaneous integrity. These findings provide compelling evidence that topical metformin promotes regenerative processes in cutaneous wounds by stimulating AMPK-mediated angiogenesis and matrix remodeling (30).

The wound healing process includes hemostasis, inflammation, proliferation, and remodeling. In addition to the angiogenesis stage, metformin regulates intracellular repair processes during wound healing, including autophagy and adaptation to hypoxia. Topical metformin appears to enhance wound healing in diabetic conditions by modulating key cellular mechanisms involved in autophagy and the hypoxic response. The research conducted by Tombulturk et al (31) revealed that metformin stimulated AMPK signaling, hence markedly enhancing the expression of autophagy markers LC3B and Beclin-1 in wound tissues. This autophagic response enhanced re-epithelialization and tissue regeneration by fostering cellular survival, proliferation and migration. Simultaneously, metformin administration resulted in a significant decrease in HIF-1α levels under hypoxic circumstances, indicating a regulatory function in sustaining cellular homeostasis throughout the healing process. Collectively, these data substantiate the mechanistic perspective that AMPK-mediated autophagy activation, in conjunction with the control of hypoxia-related pathways, underpins the therapeutic efficacy of topical metformin in addressing delayed wound healing in patients with diabetes (31).

Concurrently, immunological regulation is a vital component of the mechanisms of metformin, particularly via alterations in macrophage phenotype. Qing et al (32) demonstrated that the topical administration of metformin markedly accelerated wound healing in diabetic mice, primarily by influencing the inflammatory response via macrophage polarization. Metformin therapy facilitated a phenotypic transition from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages at the wound site, correlating with improved tissue regeneration and re-epithelialization (32). This immunomodulatory impact was mechanistically achieved by the activation of AMPK, a crucial metabolic sensor, which subsequently suppressed the mTOR signaling pathway. mTOR inhibition resulted in the decrease of NLRP3 inflammasome activation, a key contributor to persistent inflammation in diabetic wounds. Consequently, the generation of inflammatory cytokines was reduced, fostering a milieu favorable for tissue repair. These results highlight the function of metformin in facilitating macrophage-mediated resolution of inflammation and enhancing wound healing via the AMPK/mTOR/NLRP3 pathway. The topical application of metformin enhanced autophagy via the activation of the AMPK pathway. This condition suppresses the production of receptors for advanced glycation end products, inhibits NF-κB, TNF-α, and IL-6, and increases angiogenesis by releasing von Willebrand factor and vascular endothelial growth factor (32).

Metformin also increases nitric oxide production and inhibits the poly (ADP-ribose) polymerase 1 pathway through the AMPK pathway, resulting in a reduced inflammatory response. This immunomodulatory effect enhances the inhibition of traditional pro-inflammatory mediators in chronic wounds by metformin. The research conducted by Tombulturk et al (11) provides substantial data about the mechanism of topical metformin in wound healing, illustrating its anti-inflammatory activity via the modulation of NF-κB signaling. Metformin notably inhibited NF-κB p65 activity and diminished the mRNA expression levels of its downstream targets, MMP-2 and MMP-9, which are MMPs frequently overexpressed in chronic diabetic wounds and play a role in extracellular matrix degradation and compromised tissue repair. By downregulating this inflammatory cascade, metformin promotes the resolution of the extended inflammatory phase often observed in diabetic wounds, therefore allowing advancement into the proliferative phase of healing. The molecular effects align with the reported clinical consequences of expedited wound healing, establishing metformin as a potential therapeutic drug for enhancing tissue regeneration in diabetes-compromised cutaneous wounds (11).

Consistent with these findings, Cam et al (9) further demonstrated the capacity of metformin to inhibit TNF-α expression in diabetic wounds. Topically delivered metformin demonstrated anti-inflammatory effects in diabetic wound healing by significantly lowering the expression of TNF-α, a pivotal cytokine involved in sustaining the inflammatory phase of wound repair. In that study, diabetic rats treated with metformin-loaded bacterial cellulose/gelatin nanofibers exhibited a marked reduction in TNF-α levels by day 14, which corresponded with improved histological outcomes, including enhanced re-epithelialization and granulation tissue organization (9). Since TNF-α is known to delay wound progression by perpetuating macrophage-mediated inflammation, its suppression by metformin suggests a beneficial modulation of the early immune response, ultimately supporting tissue regeneration and accelerated healing in hyperglycemic conditions. These findings reinforce the therapeutic relevance of the anti-inflammatory properties of metformin in resolving chronic inflammation, a major barrier to effective wound closure in diabetic patients (9).

Moreover, metformin has been shown to support fibroblast proliferation and the development of granulation tissue. Cam et al (33) demonstrated that topical metformin significantly enhanced diabetic wound healing by modulating inflammatory cytokines and promoting fibroblast-mediated tissue repair. In that study, wounds treated with metformin-loaded gelatin nanofiber scaffolds exhibited accelerated re-epithelialization and contraction, accompanied by reduced levels of proinflammatory markers such as TNF-α. This suggests that metformin may act by inhibiting proinflammatory signaling pathways, creating a microenvironment conducive to tissue repair (33). Additionally, histological analysis revealed increased fibroblast proliferation and an improvement in the development of granulation tissue, indicating enhanced cellular regeneration. The porous structure of the scaffold also supported vascularization, further facilitating the delivery of oxygen and nutrients essential for wound closure. These combined effects highlight the multifaceted role of metformin in promoting tissue regeneration in diabetic wounds by suppressing inflammation and supporting structural healing processes (33).

In addition to its effects on fibroblasts and inflammation, metformin may also regulate fibrogenic signaling via TGF-β1. The topical application of metformin hydrochloride hydrogel has been shown to significantly accelerate wound healing by upregulating TGF-β1, a pivotal cytokine in tissue regeneration. In the study by Tawfeek et al (8), immunohistochemical analysis revealed a marked increase in TGF-β1 expression in treated wounds, particularly within fibroblasts, compared to baseline levels. This molecular enhancement was associated with the histological evidence of robust angiogenesis, fibroplasia and the complete re-epithelialization of the wound bed (8). Elevated TGF-β1 signaling is known to facilitate vascularization, stimulate extracellular matrix production, and promote keratinocyte migration, collectively contributing to faster wound closure and tissue remodeling. These findings provide valuable mechanistic support for the therapeutic use of topical metformin in cutaneous wound management, especially in cases where enhanced regenerative response is critical (8).

Notably, the suppression of TGF-β1 by metformin has also been linked to scarless wound healing. Topical methods have demonstrated significant potential in promoting scarless skin wound healing by modulating multiple fibrotic and inflammatory pathways. The study by Zhang et al (6) demonstrated that metformin activates AMPK, a central energy-sensing enzyme, which in turn leads to the downregulation of TGF-β1, a key pro-fibrotic cytokine. This suppression of TGF-β1 was associated with a marked reduction in the number of α-SMA-positive myofibroblasts, cells known to drive extracellular matrix deposition and fibrosis. Consequently, there was a decrease in collagen III expression, typically linked to disorganized scar tissue, and a concurrent increase in collagen I, indicative of organized tissue regeneration. Furthermore, metformin treatment significantly reduced the levels of pro-inflammatory markers HMGB1 and IL-1β, thereby contributing to an anti-inflammatory microenvironment favorable for healing. These findings support the mechanism whereby metformin, through AMPK activation and inflammatory suppression, fosters the development of functional, scar-free skin tissue (6).

Further supporting this finding, metformin promotes wound repair by balancing collagen synthesis and inhibiting apoptosis. According to the study by Tombultürk et al (10), the application of topical metformin enhanced wound healing in both diabetic and non-diabetic Wistar rats by exerting pro-proliferative and anti-apoptotic effects. Treated wounds exhibited faster closure and improved histological organization, which was associated with increased levels of collagen types I and III, key structural proteins involved in tissue regeneration. Additionally, metformin reduced the expression of the apoptosis-related proteins p53 and c-Jun, suggesting a decrease in programmed cell death within the wound area. These findings indicate that metformin supports the healing process by stimulating collagen production and cell proliferation while limiting apoptosis, ultimately improving wound repair outcomes across different metabolic conditions (10).

Finally, the regenerative benefits of metformin have also been explored in mechanically stressed skin models, where stem cell activation plays a key role. Xiong et al (13) found that applying topical metformin notably improved the regenerative response in mechanically stretched skin in rats. The treatment resulted in a marked increase in both epidermal and dermal thickness, accompanied by greater collagen accumulation and enhanced formation of new blood vessels. Moreover, metformin stimulated the proliferation of key skin-derived stem cells, including epidermal stem cells and hair follicle bulge stem cells, which play a crucial role in skin repair. These outcomes suggest that metformin enhances the regenerative potential of stretched skin by enhancing stem cell activity, promoting tissue remodeling, and reinforcing the structural and vascular components essential for effective skin regeneration (13).

Topical metformin has shown promising potential for managing various dermatologic conditions, particularly acne vulgaris, psoriasis, and alopecia, by targeting both inflammatory and metabolic pathways. Emerging research has identified metformin as a potential topical agent for acne due to its diverse pharmacological actions beyond glucose control. If delivered through the skin, metformin demonstrates anti-inflammatory, lipid-reducing (sebo-suppressive), and antioxidant activities that directly address the key pathological elements of acne (34). Metformin reduces lesion severity by modulating insulin resistance, androgen levels and local inflammation, primarily through the inhibition of the NF-κB signaling pathway and the suppression of pro-inflammatory cytokines, such as IL-6 and TNF-α. Its topical application has been shown to improve clinical outcomes with minimal irritation, offering a safe alternative or adjunct to traditional acne therapies (12). In psoriasis, metformin acts through the AMPK/mTOR signaling axis to inhibit keratinocyte hyperproliferation, suppress oxidative stress, and promote apoptosis in overactive epidermal layers (35). These effects are particularly beneficial in patients with comorbid metabolic syndrome, as metformin also helps regulate glucose and lipid metabolism. As regards alopecia, recent studies suggest that metformin may support hair follicle regeneration by enhancing perifollicular angiogenesis and suppressing perifollicular inflammation, although more data are needed to confirm this benefit (36). Collectively, these findings highlight the versatility and mechanistic depth of metformin as a topical treatment for chronic skin disorders characterized by dysregulated immune or metabolic activity.

Clinical relevance and translational perspectives. Recent clinical trials have highlighted the therapeutic potential of topical metformin in dermatology. A 30% metformin cream has shown efficacy in treating melasma, with results comparable to conventional treatments but fewer adverse effects, such as irritation or erythema (5). Similarly, a 0.6% hydrogel for wound healing demonstrated the ability to accelerate tissue regeneration, enhance collagen synthesis, and reduce inflammation (7). These studies support the promising role of topical metformin in managing conditions, such as hyperpigmentation and chronic wounds, particularly in diabetic patients.

Recent innovations in topical drug delivery have been explored to address the limited skin permeability of metformin due to its hydrophilic nature and high polarity. These advanced formulations allow for more targeted and sustained drug release within the sebaceous units, thereby improving therapeutic outcomes and minimizing systemic exposure (8). Mousa et al (20) found that ethosomal gels significantly increased metformin's skin bioavailability, and other formulations, such as nanofibers and hydrogels, have also shown promise in improving localized drug delivery (8,20). Although these formulations have proven to be safe in clinical trials with minimal adverse effects, further research is needed to assess the long-term safety and optimal dosing of topical metformin, especially for broader patient populations and more chronic use.

In conclusion, the main purpose of metformin is to treat type 2 diabetes. In the present scoping review, it was demonstrated that metformin is a potential topical treatment for wound healing, melanoma, and UVA- and UVB-induced aging of the skin, in addition to being an oral anti-diabetic drug. This information has been used to evaluate the possible modes of action of each effect. Topical metformin has anti-melanogenic properties on human skin biopsies and epidermis. It also possesses anti-inflammatory, anti-apoptotic, antioxidant, and anti-photoaging properties. Topical metformin was previously shown to function only as an antagonist in pigmentation in animal studies (37); nevertheless, there have recently been hopeful reports in cutaneous malignancies and hyperpigmentation diseases, including melanoma (21).

In preclinical studies, topical metformin has demonstrated promising therapeutic potential for various dermatologic conditions, including wound healing, hyperpigmentation, and UV-induced skin photoaging. However, the majority of these findings are based on experimental models (in vitro and in vivo). Consequently, further research in clinical trials is required to determine appropriate dosage, safety, and efficacy, as well as to identify the most effective lead compounds for human use through high-throughput analysis.