FormalPara Key Summary Points

Tirbanibulin 1% ointment has been licensed to treat non-hyperkeratotic actinic keratosis (AKs) on the face and scalp in adults to ensure excellent patient tolerability due to the mild side effects and the brief application time.

Topical treatments for AKs may inadvertently confer cosmetic benefits to patients, but the anti-aging effects of tirbanibulin 1% ointment have not yet been reported.

We report the first case series of patients seeking treatment for AKs in the context of photodamaged areas in which the application of tirbanibulin 1% ointment induced, besides clearance of AKs, anti-aging effects on both skin texture and solar lentigos.

The stunning aspect of the observations in our study is the reduction of mottled pigmentation and skin lightening after treatment with tirbanibulin 1% ointment, data not observed in any other therapy for the treatment of AKs.

Introduction

Actinic keratosis (AK) is a cutaneous intraepithelial neoplasm commonly arising in sun-exposed areas among adults, particularly on the face, scalp, and dorsal hands of predisposed individuals over the age of 40 [1]. Risk factors include older age, male gender, Fitzpatrick skin types I–II, prolonged exposure to ultraviolet (UV) radiation, use of sunbeds, prolonged periods of immunosuppression, and a previous history of AK and non-melanoma skin cancer (NMSK) [2, 3]. AKs have been classified according to the Olsen clinical classification system into three grades: grade 1 is characterized by barely visible but palpable pale pink macules, grade 2 with easily palpable and visible red and scaly lesions, and grade 3 with hyperkeratotic lesions difficult to distinguish from early cutaneous squamous cell carcinomas (cSCC) [4,5,6,7]. Among the several treatments to date available for AK management, they can be divided into “lesion-directed” and “field-directed” treatment. Lesion-directed therapies include 0.5% 5-fluorouracil (5-FU) plus 10% salicylic acid (5-FU/SA), cryotherapy, and laser dermabrasion, while field-directed treatments currently available include 4% 5-FU, 3% diclofenac in hyaluronic acid (HA), 3,75% imiquimod (IMI) cream, and photodynamic therapy (PDT). These therapies are prescribed with different schedules of application based on patient characteristics and disease severity [2]. Recently, tirbanibulin 1% ointment (Klisyri®, Almirall, S.A., Barcelona, Spain) has been licensed to treat non-hyperkeratotic AK lesions on the face and scalp in adults to ensure excellent patient tolerability due to the mild side effects and the brief application time (five consecutive days) compared to the other topical therapies on the market [8, 9]. Tirbanibulin directly binds to tubulin, triggering cell cycle arrest and apoptosis in actively dividing cells, which leads to microtubule disruption. Furthermore, it disrupts Src tyrosine kinase signaling [10]. A growing body of evidence suggests that, beyond their primary function, the treatments for AKs and the cancerization field may inadvertently confer substantial cosmetic benefits to patients. These benefits include improvements in skin texture, mitigation of photodamage, and the potential for a younger, rejuvenated skin appearance. However, although these effects are documented for some AK therapies, they have not yet been explored with the topical application of tirbanibulin 1% ointment. While data about its efficacy and safety profile are already available [11,12,13,14], its impact on photodamage, usually associated with AKs in the context of field cancerization, has recently been reported only in a recent case report [15]. On this topic, we report a retrospective case series of patients affected by AKs on the face and scalp treated with tirbanibulin 1% in which the topical treatment caused a striking amelioration of concomitant photodamage, with improvement of both wrinkles and solar lentigo.

Methods

We performed a retrospective single-center evaluation of patients treated with tirbanibulin 1% ointment at the Dermatology Unit of the University of Messina, Italy, between February and December 2023. Exclusion criteria were pregnancy and lactation, known allergies to any component of the study drug, history of photosensitivity, active infections, immunosuppression, and prior therapies with other topical treatments for AKs and photoaging in the last 12 weeks. The procedures followed here were in accordance with the Helsinki Declaration of 1964 and its later amendments. Written informed consent was obtained from all patients for their photographs and medical information to be published.

At baseline (T0), all patients underwent physical examination with the acquisition of clinical and dermoscopic images. Clinically collected data included age, gender, phototype, personal history of skin cancer, and previous treatments for AKs and skin aging (concluded at least 12 weeks before).

Patients were therefore instructed to apply tirbanibulin 1% ointment once daily for five consecutive days in sufficient quantities to cover the affected AK area with a thin layer, avoiding application on open wounds or injured skin, as indicated in the package leaflet.

Clinical pictures were recorded 57 days (T1) after the start of the treatment to evaluate its efficacy. Efficacy was evaluated as total clearance (total disappearance of lesions) or partial clearance (75% reduction of lesions). Simultaneously, local skin rejuvenation was evaluated by investigators, considering parameters such as xerosis or dehydration, wrinkles, elastosis, laxity, poikilodermia, accentuation of skin markings, skin turgor, vascular telangiectasias, and reduction of mottled pigmentation. Rejuvenation was rated according to Global Aesthetic Improvement Scale (GAIS) as follows: (1) very much improved (optimal cosmetic result); (2) much improved (marked improvement in appearance from the initial condition, but not completely optimal); (3) improved (obvious improvement in appearance from the initial condition); (4) no change; (5) worse.

Results

Seven patients affected by Olsen grade 1–2 AKs experienced powerful rejuvenating effects in the treated areas, with a marked efficacy in skin lightening and clearance of solar lentigo.

Case 1

An 80-year-old woman came to our attention for isolated crusted lesions on her right cheek. Clinical examination revealed grade 1 and 2 AKs on her cheek, in the context of chronically sun-damaged skin, with multiple solar lentigos and wrinkles (Fig. 1a). The patient had already undergone cryotherapy and two sessions of PDT, 1 year before, with only partial results and a tendency to recurrence after treatment. We prescribed tirbanibulin 1% ointment to be applied for five consecutive days in the affected areas. Since the third day of application, the patient reported the onset of local skin reactions (LSRs), with light erythema rapidly progressing to a severe erythematous-scaling reaction, accompanied by a burning sensation; however, she completed the scheduled application. The adverse reaction progressed towards full recovery within 2 weeks. At T1, complete clearance (total disappearance) of AKs was observed, together with improvement of skin texture and hyperpigmentation (Fig. 1b). In particular, significant lightening of the large solar lentigo in the lower cheek was detected. The cosmetic outcome was rated by physicians as grade 2 (much improved, not completely optimal) according to the GAIS. At 6-month follow-up, no relapse of AKs and solar lentigos was observed.

Fig. 1
figure 1

a Actinic keratosis (AKs) in the right cheek, in the context of sun-damaged skin with solar lentigos, and wrinkles; b AKs resolution with an improvement of skin elasticity, wrinkles, and lightening of solar lentigos, at 8 weeks follow-up

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Case 2

A 78-year-old woman with erythematous macules on her right cheek was referred to our department. According to the clinical and dermoscopic features of the affected skin, she was diagnosed with multiple grade 2 Olsen AKs. Additionally, the patient’s facial skin displayed significant signs of photo- and chrono-aging, such as wrinkles and laxity (Fig. 2a). A solar lentigo upon the upper lip was also observed. We prescribed tirbanibulin 1% ointment as the schedule. The patient reported no significant LSRs in the course and shortly after the treatment. At the 8-week follow-up, complete resolution of AKs was observed, together with a significant amelioration of the skin texture and appreciable reduction of skin wrinkling compared to the surrounding areas and complete lightning of the solar lentigo (Fig. 2b). The patient expressed her satisfaction with the good cosmetic outcome, which was rated by physicians as grade 2 (much improved, not completely optimal) according to the GAIS.

Fig. 2
figure 2

a Actinic keratosis (AKs) in the right cheek, in the context of sun-damaged skin with wrinkles and solar lentigo upon the lip; b AKs resolution with significant amelioration of the skin texture and an appreciable reduction of wrinkling and complete lightening of the solar lentigo upon the upper lip, at 8 weeks follow-up. The cosmetic outcome was rated by physicians as grade 2 (much improved, not completely optimal) according to the Global Aesthetic Improvement Scale (GAIS)

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Case 3

A 63-year-old man came to our attention for the onset of erythematous scaling lesions on the scalp for 2 years. Clinical examination revealed the presence of isolated grade 1 AKs in the context of photodamaged skin. Moreover, a solar lentigo, characterized by light brown typical pseudo-network and regular diffuse pigmentation, was detected (Fig. 3a). We prescribed tirbanibulin 1% ointment to be applied on the scalp, in the area of up to 25 cm2 of affected sun-damaged skin. The patient reported the onset on the fourth day of treatment of erythema rapidly progressing to a severe erythematous-scaling reaction; however, the reaction disappeared on its own around the sixth day after the end of the treatment, without the need for analgesic therapy. At T1, we observed complete resolution of AKs with lightening of the solar lentigo (Fig. 3b). The skin quality at the treatment site showed good improvement, exhibiting reduced signs of photo-aging damage compared to the surrounding area (grade 2 according to the GAIS). Only slight post-inflammatory erythema persisted.

Fig. 3
figure 3

a Olsen grade 1 actinic keratosis (AKs) of the scalp in the context of sun-damaged skin, with a large pigmented solar lentigo; b complete resolution of AKs and the solar lentigo at 2-month follow-up

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Case 4

An 80-year-old woman came to our attention for the onset of multiple slightly itchy erythematous macules with poorly defined borders and minimal hyperkeratosis on the dorsa of her nose. The perilesional skin and the checks, especially the right one, presented clinical signs of UV radiation damage, including xerosis and mottled pigmentation (Fig. 4a). Dermoscopic examination revealed Olsen grade 2 AKs in the dorsal nose and multiple solar lentigos in the nose and cheek. We prescribed tirbanibulin 1% ointment to be applied in these areas for five consecutive days. No LSR was reported by the patient. At T1, clinical and dermoscopic examination revealed complete resolution of AKs and amelioration of photoaging signs, with almost complete resolution of mottled pigmentation in the nose and cheeks, with concomitant enhanced skin turgor (Fig. 4b). The patient expressed her satisfaction with the aesthetic results. The cosmetic outcome was rated by physicians as grade 2 (much improved, not completely optimal) according to the GAIS.

Fig. 4
figure 4

a Actinic keratosis (AKs) in the dorsa of the nose in an 80-year-old woman, in the context of photodamaged skin in the cheeks and nose with mottled pigmentation and xerosis, before treatment with tirbanibulin ointment; b complete resolution of AKs in the nose and concomitant skin rejuvenation with reduction of mottled pigmentation in the nose and cheeks and enhanced skin turgor at 2-month follow-up. The cosmetic outcome was rated by physicians as grade 2 (much improved, not completely optimal) according to the Global Aesthetic Improvement Scale (GAIS)

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Case 5

An 80-year-old man came to our attention to check a brown macule in his left cheek that had been going on for many years. Clinical and dermoscopic examination revealed a solar lentigo in the context of sun-damaged skin with isolated AKs (grade 1 Olsen) (Fig. 5a). We prescribed tirbanibulin 1% ointment to be applied on the left cheek, in the area of up to 25 cm2 of affected sun-damaged skin. The patient reported the onset on the fourth day of treatment of erythema rapidly progressing to a severe erythematous-scaling reaction; however, the reaction disappeared on its own around the sixth day after the end of the treatment, without the need for analgesic therapy. Two months after the treatment, we observed a partial reduction of AKs and a concomitant complete resolution of the solar lentigo (Fig. 5b). The cosmetic outcome was rated by physicians as grade 3 according to GAIS.

Fig. 5
figure 5

a Photodamaged skin in an 80-year-old man before the tirbanibulin 1% treatment; in the left check is also visible a solar lentigo (black arrow); b complete resolution of solar lentigo (black arrow) at 57 days after the tirbanibulin application. The erythematous macule was not related to tirbanibulin but was the result of a trauma that occurred the day before the follow-up visit

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Case 6

A 65-year-old man came to our attention for multiple brownish macules on his forehead and several erythematous macules in his left cheek, from several years. Clinical examination revealed several solar lentigos and seborrheic keratoses in his forehead and cheek in the context of sun-damaged skin, with contextual multiple AKs (grade 2 Olsen) (Fig. 6a). The patient had already undergone therapy with two sessions of PDT and cryotherapy, 6 months before. We prescribed tirbanibulin 1% ointment to be applied in the areas mentioned above for five consecutive days. No LSR was reported by the patient. At 8 weeks follow-up clinical and dermoscopic examination revealed almost resolution of AKs (> 75%) and amelioration of photoaging signs, with almost complete resolution of mottled pigmentation in the cheek and forehead. Only a slight brownish lentigo in the left temporal area persisted (Fig. 6b). The patient expressed his satisfaction with the aesthetic results. The cosmetic outcome was rated by physicians as GAIS grade 1.

Fig. 6
figure 6

a A 65-year-old man with several lentigos, seborrheic keratoses, and actinic keratosis (AKs) in the context of sun-damaged skin before treatment with tirbanibulin 1% ointment; b almost complete resolution of lentigo in the cheek and forehead at 57-day follow-up

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Case 7

A 78-year-old man was referred to our department for multiple AK lesions in the face. The patient had previously undergone therapy with topical 4% 5-FU for four consecutive weeks, 1 year before, with good results but recurrence of the disease after 6 months. Clinical examination revealed isolated AKs (Olsen 1) in the face, in the context of photodamaged skin, with a large solar lentigo in the left cheek and small solar lentigos left frontal area (Fig. 7a). We prescribed tirbanibulin 1% ointment to be applied to the left cheek and left frontal area for five consecutive days. At T1 complete resolution of AKs was detected; concurrently we observed a surprisingly complete lightening of the solar lentigos of the cheek and the frontal area. The patient expressed his satisfaction with the aesthetic results. The cosmetic outcome was rated by physicians as grade 1 (very much improved, optimal cosmetic result) according to the GAIS. At 6-month follow-up, no recurrence of AK lesion and solar lentigo was detected (Fig. 7b).

Fig. 7
figure 7

a Multiple Olsen grade 1 actinic keratosis (AKs) in the face of a 78-year-old man, in the context of photodamaged skin, with a large solar lentigo in the left cheek and small solar lentigos left frontal area before treatment with tirbanibulin ointment; b complete resolution of AKs at T1, with complete lightening of the solar lentigos of the cheek and the frontal area

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Discussion

Skin aging, depending on both chronological processes (intrinsic aging) and external factors (extrinsic aging), represents the most evident sign of human aging [16, 17]. Intrinsic aging is a physiological process characterized by reduced cell proliferation in the basal layers and accumulation of senescent cells in the epidermis and dermis, characterized by skin dryness, thinning, fine wrinkles, xerosis, and itching, as well as susceptibility to several cutaneous disorders, including infections, autoimmune diseases, and tumors [18]. Conversely, extrinsic aging depends on external factors, including pollutants, smoking, dietary habits, and especially exposure to UV and infrared radiation. These factors influence the onset of inflammation and aging phenotypes such as wrinkles, irregular pigmentation, dry skin, and decreased thickness of the dermis and epidermis [19]. Chronic exposure to UV rays, emitted by the sun and artificial sources, at a high dosage causes sunburn, while at a lower dosage causes tanning and accelerates skin aging, called “photoaging” [20, 21]. Overall, chronic UV exposure leads to increased levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which in turn generates reactive oxygen species (ROS), increases inflammation, and finally causes skin aging [19]. The organism has defense mechanisms against oxidizing substances. However, when these are exceeded, oxidative damage mechanisms are established, degrading collagen and elastin fibers and ultimately leading to premature aging. Dermis is also subject to UVB-induced modifications. It is composed of elastic fibers, nerves, blood vessels, hair follicles, and glands, with type I collagen being the most important component [22]. The photoaged dermis is mostly characterized by a reduced collagen content, with disorganized and fragmented collagen fibers; the elastic fibers are damaged leading to the formation of visible signs of skin aging, including wrinkles, skin atrophy, and delayed wound healing. Another sign is solar elastosis, characterized by dystrophic elastotic material within the dermis [23]. Upon exposure to UVB, collagen fibrils, and elastin fibers are damaged, primarily following the synthesis of matrix-degrading metalloproteinases (MMPs), a family of ubiquitous endopeptidases, via MAP kinase signaling [16]. It has been observed that MMPs are responsible for collagen degradation, mainly through MMP-1, MMP-3, and MMP-9, through direct and complete degradation of collagen [24]. UV rays can also reduce the synthesis of procollagen, the precursor molecule of collagen, through the downregulation of the transforming growth factor (TGF)-β type II receptor (TβRII) and the TGFβ/Smad signaling pathway [25].

The management of AKs and the concurrent presence of photoaging represents a critical challenge for dermatologists. Our case series confirms that tirbanibulin 1% ointment is successful in treating AKs while also delivering notable advantages in terms of skin rejuvenation. While the anti-aging effects of other therapies for the treatment of AKs and the concomitant field of cancerization have been reported in the literature, to the best of our knowledge, case series on the anti-aging effect of tirbanibulin ointment have not yet been reported.

Among the topical therapies, 4% 5-FU is a pyrimidine analogue which, through irreversible inactivation of thymidylate synthase, interferes with DNA synthesis thus causing apoptosis of the highly proliferative AK cells. Despite its good efficacy with complete clearance response (CCR) and partial clearance response (PCR) rates ranging between 24% and 74%, its main limitation is the common onset of moderate to severe LSRs [26]. Moving to its anti-aging effects, 5-FU therapy seems to trigger epidermal injury, followed by subsequent wound healing and the promotion of dermal matrix remodeling, which ultimately leads to an improved skin appearance. Sachs et al. [27] highlighted that keratin 16, a marker of epidermal injury, interleukin-1β, a marker of inflammation, and MMP-1 and MMP-3 were significantly higher in a pool of patients treated with 5-FU. The effectiveness of 5-FU has also been demonstrated in the treatment of photodamage of the arms. A study comparing the effectiveness of 5-FU in cream or peel on 32 patients demonstrated the anti-aging effect of this treatment, both in cream and peel form, through the improvement of the skin appearance and the reduction of the dermal elastotic material. Biopsies were also performed showing reduced levels of epidermal p53 and an increase in the level of procollagen I [28]. Conversely, a secondary analysis of data from a randomized trial involving 932 veterans who received topical 5-FU treatment for NMSC chemoprevention revealed no significant difference in photodamage between baseline and post-treatment assessments at 6, 12, and 18 months, respectively [29]. However, these data do not allow us to reach definitive conclusions regarding the efficacy of 5-FU in anti-aging treatment.

Conversely, 5-FU/SA cream, evaluated in a randomized controlled trial for slightly palpable and moderately thick hyperkeratotic AK lesions, achieved a CCR of 49.5% 8 weeks after the 12-week treatment period. However, the onset of LSRs, correlated with treatment duration and efficacy, represented a major limitation [30]. Poor data are currently available about the effects of 5-FU/SA on skin rejuvenation. Recently an Italian study reported excellent aesthetic improvement after 5-FU/SA cream in a 77-year-old woman with the disappearance of AKs and improved skin appearance [31].

Diclofenac 3% in HA, a nonsteroidal anti-inflammatory drug with increased affinity for cyclooxygenase (COX)-2, is a field treatment well tolerated by patients but with limited efficacy in AK clearance, especially in thick lesions, with a 1-year CCR ranging between 18% and 29%. Another limitation is the reduced compliance of the patients, due to the twice daily application according to the technical data sheet [32, 33]. Regarding the anti-aging efficacy, some authors have reported a reduction in the area affected by seborrheic keratoses following therapy with diclofenac [34]. Other authors reported complete clearance of seborrheic keratosis in a 73-year-old man treated with diclofenac 3% twice a day for 1 month; however, the authors failed to explain the mechanism of action of diclofenac on seborrheic lesions [35].

IMI cream, a topical immunomodulator, activates Toll-like receptor 7 (TLR7), leading to increased cytokine production, particularly interferon-α (IFNα) and tumor necrosis factor alpha (TNFα), which helps to eliminate abnormal or damaged cells associated with AKs [2]. IMI is available as a 5% cream to be applied three times weekly for 12–16 weeks, or a 3.75% cream. Placebo-controlled studies demonstrated the efficacy of 3.75% IMI cream, achieving CCR ranging between 34% and 59.5% for AKs on the face and scalp [36]. To date, some shreds of evidence are available to confirm the rejuvenating effect of IMI cream. A study conducted by Metcalf et al. demonstrated a significant increase in papillary dermal fibroplasia with an associated reduction in solar elastosis and restoration of normal epidermal thickness after IMI cream treatment [37]. Finally, a prospective non-comparative pilot study demonstrated the anti-aging effect of IMI 5% cream in 72.7% of patients who applied the treatment on the periorbital skin, based on the self-assessed 5-point Likert scale [38].

PDT, based on the topical application of 5-aminolevulinic acid (ALA) or its methylated ester (MAL) and irradiation with red light (approx. 630 nm), stimulates ROS production for the selective destruction of cells with a high metabolic state, including inflammatory, infectious, and cancerous ones, which explains its wide range of clinical applications [39,40,41,42,43,44]. Pooled data from three studies, with up to two treatments of red-light ALA-PDT, showed baseline lesion resolution rates of 89.1% and 32.7% at 12 weeks post-treatment for patients with AK administered ALA-PDT and placebo-PDT, respectively [45,46,47]. The anti-aging effects of PDT are already reported in the latest guidelines with recommendation strength A and quality of evidence I [7]. PDT promotes significant improvement in fine wrinkles, mottled pigmentation, sallow complexion, skin texture, tactile roughness, telangiectasias, and facial erythema. PDT has been demonstrated to cause an increase in type I collagen and a decrease in elastotic material in the dermis, effectively reversing signs of photoaging [7, 23, 48, 49]. In vitro studies have shown that PDT can enhance the production of collagen type I and collagen-degrading MMP-3 by activating extracellular signal-regulated kinase [49]. It has been suggested that the increase in MMP-3 may facilitate the degradation and removal of old, damaged collagen fibers, while fibroblasts initiate the formation of new ones to replace them. The interaction between epithelial and mesenchymal cells appears to be crucial in PDT-induced photorejuvenation, with keratinocytes inducing cytokines that stimulate collagen synthesis in fibroblasts [50]. Additionally, collagen remodeling after PDT is stimulated by the release of TGFβ1 in keratinocytes [51]. The inhibition of melanogenesis through paracrine effects by keratinocytes and fibroblasts may also contribute to the improvement of mottled hyperpigmentations following PDT.

Tirbanibulin is a newly developed synthetic chemical anti-proliferative agent that inhibits tubulin polymerization, which represents a crucial step for cell migration, protein transport, and cell division. It induces the expression of p53, which leads to cell cycle arrest at the G2/M phase, and triggers apoptosis through several intrinsic and extrinsic pathways including hyperphosphorylation of Bcl-2, cleavage of caspases 8 and 9, activation of caspase 3, and cleavage of poly(ADP-ribose) polymerase [52]. Additionally, tirbanibulin inhibits oncogenes, especially Src family kinase signaling, which causes proliferation and progression to cSCCs, thus reducing cancerous cell migration, proliferation, and survival [53]. In pivotal phase 3 trials, tirbanibulin demonstrated efficacy with CCR achieved in 44–54% of patients and 76–82% of lesions [8]. These findings were supported also by our real-world data, showing half of the lesions achieving CCR and nearly two-thirds showing PCR [14]. A recent meta-analysis conducted by Heppt et al. demonstrated that tirbanibulin performs with a good safety profile and efficacy, comparable with existing topical treatments currently available in Europe, but with a shorter treatment period which represents its greatest step forward [9]. Moreover, in a Scottish economic evaluation, tirbanibulin was cost saving when compared to diclofenac, IMI, and 5-FU [54]. The 2021 American Academy of Dermatology guidelines awarded tirbanibulin the highest recommendation for topical treatment due to its shorter treatment cycle and tolerable local skin reactions [2]. Since tirbanibulin induces apoptosis and not necrosis of transformed keratinocytes, it leads to the activation of inflammatory cells with the consequent release of cytokines in lower levels compared to other field therapies, which ensures mild LSRs and good tolerability. In fact, from the literature data it emerges that, although 5-FU is the drug that performs better, tirbanibulin is the therapeutic choice that guarantees fewer side effects and better tolerability by patients [55]. Furthermore, recent real-life studies are highlighting the wide range of possible applications of tirbanibulin, beyond actinic keratoses. Therapeutic efficacy has been reported both in the treatment of NMSCs, including basal cell carcinoma and Bowen disease, and in the treatment of anogenital warts and vulvar intraepithelial neoplasia [56,57,58].

Moving to the anti-aging effects, to date, only a case report has recently been reported about the efficacy of tirbanibulin ointment in a 78-year-old man with multiple flat, erythematous, scaly lesions on the scalp, with solar lentigos the field of cancerization as well [15]. After 2 months, clearance of AKs and solar lentigo was detected in the field of application. Aesthetic improvement following therapy with tirbanibulin ointment is an intriguing new observation not yet explored.

To the best of our knowledge, we reported the first real-life experience on the anti-aging efficacy of tirbanibulin 1% ointment in the context of the treatment of AKs and the cancerization field. While on the one hand, the effectiveness and tolerability of this new drug have been confirmed, both in clinical trials and in real-life settings, on the other hand, its effectiveness in improving skin texture and reducing hyperpigmentation associated with actinic damage has still not emerged. The most stunning aspect of the observations in our study is the reduction of mottled pigmentation and the “skin-lightening effect” of tirbanibulin, data not previously observed in any other therapy for the treatment of AKs. In fact, in other therapies, an anti-aging effect with reduction of wrinkles has been mostly observed, but a lightening of the skin is not reported. We hypothesize that the improvement of skin wrinkles and texture observed in our patients could be at least in part explained by the enhanced collagen production, stimulated by the release of inflammatory cytokines in the dermis, including TGFβ, while the mechanism underlying the lightening of pigmentary spots is not yet clear. We may suggest that the skin-lightening effects may be correlated to the capacity of tirbanibulin to activate intrinsic and extrinsic apoptotic pathways that cause the removal of the increased melanocyte units present in solar lentigos. Following this hypothesis, an in vitro antiproliferative effect of tirbanibulin has been demonstrated by a cell viability assay, in a panel of tumor cell lines including malignant melanocytic lesions such as melanoma, after 72 h of incubation [53].

However, our study presents several limitations. Firstly, the sample size was small, highlighting the need for a larger real-world experience to validate our findings. Additionally, the relatively short follow-up period warrants further investigation, ideally with a period of 1 year to assess the sustainability of outcomes and observe any potential disease recurrence rates. Furthermore, the absence of a control group presents challenges in making direct comparisons between the treated group and those receiving no intervention, which hampers our ability to definitively attribute the observed outcomes solely to the treatment under investigation. Future studies addressing these limitations would provide valuable insights into the efficacy and long-term effects of the intervention.

Finally, in vivo studies are necessary to fully understand tirbanibulin’s molecular mechanisms of action, not only focusing on antitumoral effects but also on its potential anti-aging activity.

Conclusions

Tirbanibulin 1% ointment seems able to improve skin aging as a desirable side effect at the site of application for AKs on chronic photodamaged skin. Our study provides evidence, albeit preliminary, about the potential anti-aging efficacy, in concert with the anti-tumor efficacy, of tirbanibulin 1% ointment. The patients observed in our real-life experience showed a great improvement in skin texture, reduction of wrinkles, and, above all, reduction of pigmented lesions following the therapy. The most stunning aspect of our observations is the reduction of mottled pigmentation and skin lightening, data not observed in any other therapy for the treatment of AKs. However, further studies are necessary to understand and explore the mechanisms causing this improvement giving patients the possibility of killing two birds with one stone, resolving the pathology and, at the same time, improving skin appearance.