UV radiation induces direct DNA damage via the formation of cyclobutane pyrimidine dimers (CPDs), and other mutations. UVR also indirectly damages the DNA through the actions of ROS and reactive nitrogen species [17]. Based on research conducted by Rybchyn et al. [39], unscheduled DNA synthesis was enhanced when UV irradiated human keratinocytes were treated with 1,25(OH)₂D. Calcitriol increases the energy availability via enhanced glycolysis and activation of energy conserving processes such as mitophagy and autophagy, thus facilitating the repair of CPD. The treatment with over-irradiated metabolite derivatives 24-hydroxylumisterol₃ [24(OH)L₃] or 1,25(OH)₂D at 1 × 10⁻¹⁰ M and higher concentrations have significantly reduced UV induced CPDs (P < 0.01) and 8-OHdG (P < 0.05) in UV-irradiated keratinocytes. These treatments have considerably increased (P < 0.05) ATP levels and extracellular acidification rate in the keratinocytes when compared with the UV vehicle [40]. Several other studies have also indicated the ability of 1,25(OH)₂D to reduce UV-induced DNA damage in the skin [41–43].

Vitamin D and its analogs carry the ability to reverse the UV-induced oxidative stress, which plays a major role in skin photoaging. In a study [44] conducted using human epidermal keratinocytes, vitamin D₃, and lumisterol metabolites; 20(OH)D₃, 1,20(OH)₂D₃, 20,23(OH)₂D₃, 1,20,23(OH)₃D₃, lumisterol, 20(OH)L₃, 22(OH)L₃, 20,22(OH)₂L₃, and 24(OH)L₃ reversed UVB-mediated ROS production, in a dose-dependent manner. At 100 nM concentration, all tested derivatives significantly reduced oxidant formation in UVB-irradiated (50 mJ/cm²) human epidermal keratinocytes. Further, this study evidenced the involvement of protective mechanisms including the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidant responses, p53-phosphorylation, and the induction of DNA repair for UV-induced cellular damage [44]. Nrf2 is a redox sensitive transcription factor that regulates cellular antioxidant defense responses against UV radiation and other environmental stresses [45]. Generally, the level of Nrf2 regulated antioxidant genes rapidly declines upon UV exposure in keratinocytes. The treatment with vitamin D₃ and lumisterol derivatives strongly induced Nrf2 protein expression, mainly in the nucleus [44].

Vitamin D₃ also protects the skin against photoaging by regulating p53 mediated pathways. The tumor suppressor protein p53 is activated upon exposure to UV radiation to control cellular responses to DNA damage. Activation of p53 enhances nucleotide excision repair and promotes G1 phase cell cycle arrest to repair damaged DNA before replication. Further, p53 also contributes to the complex regulation of cellular antioxidant defense mechanisms and apoptosis of cells with irreparable DNA damage [46, 47]. The nuclear p53 level significantly increased in 1,25(OH)₂D treated keratinocytes after UVR exposure (P < 0.01), when compared to untreated keratinocytes [46].

The free radical NO is produced from L-arginine by the activation of NO synthase upon skin exposure to UV radiation. Higher concentrations of NO can cause DNA damage and lipid peroxidation by acting as a free radical or combining with superoxide to generate a cytotoxic oxidant, peroxynitrite (ONOO^–). Peroxynitrite causes DNA base damage predominantly at G and 8-oxoG nucleobases, producing a variety of nitration and oxidation products [48]. Peroxynitrite also activates the nuclear nick sensor enzyme, poly(ADP-ribose) polymerase (PARP), reducing cellular NAD⁺ and ATP levels in the skin, leading to necrotic cell death [49]. Excess levels of NO can further inhibit nucleotide excision repair, activate mitochondrial apoptotic pathways, and function as a pro and anti-apoptotic modulator in a situation-based manner [47, 50]. Treatment of human keratinocytes with 1,25(OH)₂D prior to UV irradiation reduces NO products, providing protection against antioxidant damage from UV [46].

Calcitriol further protects the skin cells against UV-mediated oxidative stress by inducing the radical scavenger metallothionein (MT). The photo-protective effect of MTs was validated by the observation that the skin of MT-null mice acquired a greater number of sunburns and apoptotic cells than normal mice, after UVB irradiation [51]. A study conducted by Karasawa et al. [52] demonstrated that MT mRNA was induced by 1,25(OH)₂D in a dose-dependent manner, in cultured epidermal keratinocytes and in liver, kidney, and skin tissues in vivo. Lee and Youn [53] also confirmed the 1,25(OH)₂D mediated induction in expression of MT, in the basal layer of mice skin.

Vitamin D also protects the cells against oxidative stress by activating antioxidative enzymes. The defense enzymes superoxide dismutase, catalase, and glutathione peroxidase scavenge excess ROS and decrease the intracellular levels of malondialdehyde, mitigating oxidative stress [54–56].

The effect of vitamin D in modulating innate and adaptive immune systems is well documented. Since inflammation is a major contributor to UV-induced photo-damage, protection from vitamin D is immensely beneficial in combating photoaging. The skin progresses through three pathological phases after UV exposure. The early vasodilatory phase involves increased blood flow, edema, erythema, and pain sensitivity. In the second inflammatory phase, neutrophils, monocytes and T cells accumulate in the skin along with increased expression and release of pro-inflammatory cytokines. The third resolution phase contains many anti-inflammatory events to counteract the acute inflammation. Anti-inflammatory cytokines such as IL-4, IL-10, TGF-β are secreted from the skin at this stage [25]. It has been shown that UVR treatment increases the secretion of IL-10 and TGF-β cytokines in human keratinocytes [57, 58]. Calcitriol counteracts the inflammatory responses to UV photo-damage by suppressing inflammatory cytokines such as TNF, IL-1, interferon-gamma, and IL-2a while enhancing anti-inflammatory cytokines IL-4 and IL-10 [13, 59]. The proposed mechanisms through which vitamin D exerts its protective role against photoaging and skin diseases are depicted in Figure 3. The association between vitamin D and various dermatological conditions will be discussed in the next section.

Psoriasis is a chronic inflammatory autoimmune disease characterized by hyperproliferative epidermis with abnormal differentiation of keratinocytes. Erythematous skin plaques covered by hyperkeratotic scales are the main representations of the disease. Numerous epidemiological studies have suggested the possibility of an association between serum 25(OH)D levels and psoriasis [79–82].

In the meta-analysis conducted by Formisano et al. [79], psoriasis patients exhibited significantly lower serum 25(OH)D levels (21.0 ± 8.3 ng/dL) than controls (27.3 ± 9.8 ng/dL, P < 0.00001). In a case-controlled study with 120 psoriasis patients, Pokharel et al. [83] observed a statistically significant difference in the mean serum vitamin D levels in psoriatic patients than healthy controls (19.57 ± 6.85 ng/mL and 23.63 ± 6.40 ng/mL). Moreover, several review articles have also summarized topical vitamin D analogs as a successful treatment for psoriasis [84, 85]. In a systemic review, Zhao et al. [86] analyzed the success in psoriasis vulgaris treatment of vitamin D₃ analog calcipotriol, and the combination of betamethasone dipropionate (500 µg/g) and calcipotriol (50 µg/g). Clinical observations suggested that the topical calcipotriol was well tolerated and efficacious for up to 20 weeks on a fixed-treatment regimen or up to 1 year when applied as needed. However, in the long-term application, calcipotriol/betamethasone dipropionate combination was more effective than calcipotriol alone [86]. Multiple research studies have also observed the success of oral vitamin D supplementation in treating psoriasis [87–90].

Rosacea is a chronic inflammatory skin disorder where patients experience redness, flushing, visible blood vessels, burning, and tingling sensations on the face. The association of rosacea and serum 25(OH)D level was previously investigated with mixed results. Some studies have indicated that the level of serum 25(OH)D was higher in rosacea patients [62], while others have reported the opposite with patients having low serum 25(OH)D levels [91]. A recent population-based cohort study utilizing 370,209 individuals from the United Kingdom indicated an inverse association between elevated serum 25(OH)D levels and risk of rosacea development, implicating the protective role of vitamin D against rosacea [63]. However, due to the mixed nature of observations, further investigations are required to determine the possible effect of vitamin D on rosacea.

Seborrheic dermatitis (SD) is another chronic inflammatory skin disease with a papulosquamous morphology, commonly affecting the scalp, face, and body folds. It is believed that an abnormal focal inflammatory immune response to metabolites of Malassezia yeast species, and enhanced sebaceous gland activity trigger SD. The common trend of SD is to increase the severity in winter and improve in summer with exposure to UV rays [64, 92]. Due to this periodic pattern, a correlation between vitamin D levels and SD was speculated and investigated in multiple studies. Numerous studies have shown the occurrence of vitamin D deficiency in SD patients [64, 65]. In a recent study, Akbaş et al. [64] demonstrated the association of earlier onset of SD with severe vitamin D deficiency (< 20 ng/mL), suggesting lower vitamin D levels as a risk factor for SD. The supplementation of vitamin D in treating SD has provided mixed results. In an early study, topical calcipotriol treatment failed to provide significant improvements for facial SD, allowing authors to conclude that it is ineffective against facial SD [92]. However, many subsequent studies have provided evidence for the protective effect of vitamin D supplements for SD. In a small scale clinical study conducted by Dimitrova et al. [93], supplementation of oral 1,600 IU cholecalciferol per day for 3 months reduced the recurrence of SD by 65.6%, in a patient group with low levels of serum 25(OH)D. The author observed that the patients who did not respond to the supplementation had higher baseline mean values of 25(OH)D, emphasizing that supplementation of cholecalciferol could be a viable option for patients with vitamin D deficiency [93]. In an early Japanese open trial, application of tacalcitol (1,24-dihydroxycholecalciferol) twice daily produced a 73% marked improvement in facial SD [94]. Basak and Ergin [95] divided sixty patients into two equal groups and treated with either calcipotriol (50 µg/mL) or betamethasone 17-valerate (1 mg/mL) solution twice daily for four weeks. Although both treatments displayed successful results, the betamethasone 17-valerate treatment was superior to that of calcipotriol treatment in all aspects.

In a retrospective study in Malaysia [96], 32 patients diagnosed with scalp SD were supplemented with twice-weekly doses of calcipotriol plus betamethasone dipropionate (CBD) gel (50 µg of calcipotriol plus 0.5 mg of betamethasone dipropionate per g of gel). After two weeks, more than 50% of the patients showed marked improvements and by the sixth week, 40.6% of the patients achieved complete clearance. After 10 weeks, 87.5% of the patients achieved complete clearance or marked improvements, proving the efficacy of the treatment.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease affecting children and adults [97]. It is characterized by itchy, dry skin with eczematous plaques [98]. The risk factors associated with AD are genetic predisposition, epidermal dysfunction, and inflammation [99]. Multiple studies have examined the influence of vitamin D in the development of AD. Based on a study conducted in Brazil, 76.3% of the 152 AD patients indicated insufficient or deficient serum vitamin D levels [99]. In a Ukrainian study of 48 patients, vitamin D deficiency was observed among 62.5% of moderate and 90.9% of severe AD patients [100]. A study conducted in Türkiye [98] involving 96 AD patients and 90 healthy controls revealed that 58.3% of patients suffered from vitamin D deficiency. The level of vitamin D was statistically lower in severe AD patients than in mild or moderate patient groups. The authors also indicated that for each increment unit in serum vitamin D levels, the scoring atopic dermatitis (SCORAD) index decreased by 0.449 units emphasizing the protective role of vitamin D. In a meta-analysis conducted using 11 AD studies, Hattangdi-Haridas et al. [66]. identified a mean reduction in serum vitamin D concentration of 14 nmol/L in adults and 16 nmol/L in pediatric patients. When vitamin D level was measured in 41 pediatric and adult patients in Bangladesh, insufficiency and deficiency was detected in 75.6% of the AD patients [67]. Similar other studies conducted in Korea [101, 102], Canada [103], Poland [104] have also revealed an association between the severity of AD and lower vitamin D levels.

Furthermore, in a study conducted in Brazil, 116 AD patients received weekly oral vitamin D supplementation of 15,000 IU or 50,000 IU over 4 weeks, followed by a weekly 15,000 IU maintenance dose until three months. This raised their mean vitamin D level to 35.9 ng/mL compared to a baseline of 23.7 ng/mL (P < 0.001) while reducing the SCORAD index, and improving the categorization of AD in 82.7% of patients [99]. In a double blind, randomized placebo-controlled trial in Egypt, 92 pediatric patients were supplemented either with vitamin D₃ 1,600 IU/day or placebo plus baseline therapy of topical 1% hydrocortisone cream twice daily for 3 months. At the end of the treatment, serum vitamin D levels significantly improved in the treatment group along with a significant reduction in eczema area and severity index (EASI) score (20.42 ± 14.6 vs. 27.47 ± 10.11 P = 0.035) [105]. Based on a meta-analysis of five randomized controlled trials involving 304 patients, Park et al. [97] observed that the pediatric and adult patients’ SCORAD index and EASI scores significantly decreased in the vitamin D supplemented group when compared to the placebo. When supplemented with vitamin D, significant improvements could be observed in severe AD patients than that of individuals with moderate to mild AD. Moreover, high vitamin D doses such as > 2,000 IU/day accounted for favorable outcomes in the control of AD severity, whereas dosing of ≤ 2,000 IU/day failed to significantly control AD.

Ichthyoses are a group of genetic disorders characterized by scaling, hyperkeratosis, dry skin, palmoplantar keratoderma, and erythroderma due to gene mutations associated with skin barrier formation. Inherited ichthyosis can be classified into ichthyosis syndromes and non-syndromic ichthyosis, where symptoms are visible only on the skin [106, 107]. A European study reported the serum 25(OH)D levels of 87 patients with inherited ichthyosis in which vitamin D deficiency was detected in harlequin ichthyosis (n = 2; median 25(OH)D = 7.0 ng/mL), rare syndromic subtypes (n = 3; 7.0 ng/mL), and keratinopathic ichthyosis (n = 17; 10.5 ng/mL). Reduced vitamin D levels were detected in transglutaminase-1 (TG1) proficient lamellar ichthyosis (n = 15; 8.9 ng/mL), Netherton syndrome (n = 7; 10.7 ng/mL), TG1-deficient lamellar ichthyosis (n = 12; 11.7 ng/mL), congenital ichthyosiform erythroderma (n = 13; 12.4 ng/mL), and X-linked ichthyosis (n = 8; 13.9 ng/mL). The median serum 25(OH)D level in ichthyosis vulgaris patients was 19.7 ng/mL (n = 10) indicating a deficiency, yet a relatively higher value compared to other types. Overall, the median 25(OH)D level of all the patients was 12.6 ng/mL, while 32 patients were deficient, 47 were insufficient, and 6 were normal with the serum vitamin D level [69]. A study conducted in France [108], the serum vitamin D level of 53 ichthyosis patients was determined. Of them, 88.7% of patients showed vitamin D levels below the optimum level of 30 ng/mL, 34% between 20–30 ng/mL, 26.4% between 10–20 ng/mL, and 28.3% < 10 ng/mL.

In a study conducted in India [109], seven severely vitamin D deficient children (< 4 ng/mL) with congenital ichthyosis (5 with autosomal recessive congenital ichthyosis; 2 with epidermolytic ichthyosis), were supplemented with a daily dose of 60,000 IU oral cholecalciferol for 10 days followed by a maintenance dose of 400 to 600 IU of cholecalciferol. During the vitamin D treatment, significant improvement in scaling was achieved by day 5, while further improvements were achieved by day 10 in 6 patients out of 7. The skin became near normal in all the cases of autosomal recessive congenital ichthyosis. This study emphasizes the remarkable clinical improvements of pediatric patients with ichthyosis by vitamin D supplementation, proving the clinical potential of vitamin D for pigmented skin types. However, few previous studies have indicated mixed results with vitamin D treatments in patients with ichthyosis. Topical calcipotriene 0.005% ointment was effective in treating one pediatric ichthyosis patient in Africa, displaying softening of the skin and desquamation after 6 weeks of the treatment. However, according to the same study, the skin condition was not improved in another patient when vitamin D₃ is supplemented intramuscularly (600,000 IU) [110].

Vitiligo is a common skin disorder characterized by depigmented patches on the skin due to destruction of melanocytes [71]. The etiology of the disease is multifactorial, with autoimmunity playing a significant role, along with the complex interactions of inflammatory, genetic, neural, and environmental factors [73]. Due to the immune protective and melanogenic effect of vitamin D, many studies have investigated its impact on controlling vitiligo.

In a cross-sectional case-control study involving 46 patients with vitiligo, significantly lower vitamin D levels were observed in patients when compared with healthy controls (P < 0.05) [111]. In a systematic review and meta-analysis, Upala and Sanguankeo [112] analyzed data from 1,200 patients from seven selected studies. Based on the analysis, the patient group’s pooled mean 25(OH)D level was significantly lower by 7.45 ng/mL, when compared to controls (P = 0.01) [112]. A meta-analysis that summarized data from 679 patients reported a positive association between serum 25(OH)D deficiency and the incidence of vitiligo [113]. However, no significant difference in the mean serum 25(OH)D level was detected between the vitiligo patients and the general population in Korea. When further analyzed, the authors observed a significant difference in the 25(OH)D level based on the disease duration and family history [114]. An Iranian study employing 98 patients and 98 age and gender-matched healthy individuals also failed to identify a significant difference in vitamin D levels between the patient and healthy groups [73]. In a systematic review which analyzed 27 randomized controlled trials (n = 1,198), calcipotriol was indicated as the most widely used (70%) topical vitamin D analogue for vitiligo, while tacalcitol and cholecalciferol accounted for 22% and 8%, respectively [115]. The effect of vitamin D in treating vitiligo has been investigated either as monotherapy or in combinations with phototherapy, including psoralen plus UVA (PUVA), narrow-band UVB (NB-UVB), or 308 nm excimer laser (EL). In a quasi-experimental study, 32 patients suffering from vitiligo were treated with systemic PUVA thrice weekly along with topical calcipotriol twice daily to only one side of the body. Based on the observations, the calcipotriol and PUVA treated-side displayed better results than PUVA alone, indicating the efficacy of mixed treatment [116].

Liu et al. [117] conducted a meta-analysis of fourteen studies (n = 642) and found that the combined effect of either calcipotriol or tacalcitol with NB-UVB provided superior outcomes to that of NB-UVB monotherapy alone. The authors also stated that when combined with NB-UVB treatment, tacalcitol exhibited better response to treatment than calcipotriol. However, none of the vitamin D analogs could enhance the efficacy of PUVA or EL treatments for vitiligo.

In another study, Kim et al. [118] compared the efficacy of vitamin D supplementation with an EL alone or as a combined therapy with vitamin D. The 26 patients employed in this study were randomly divided into two groups; the test group obtaining 308 nm EL with cholecalciferol injection, and the control group just with the laser treatment. After six months of treatment, 83.6% of patients in the test group displayed improvements in the vitiligo area scoring index (VASI) scores, whereas the control group showed a 54.7% improvement. They also concluded that significantly more patients in the combined group achieved VASI50 and VASI75 scores, indicating better improvements.

Alopecia areata (AA) is an autoimmune disorder characterized by sudden patchy hair loss in any hair-bearing area of the body. This condition usually begins in children and young adults, though can start at any age despite of the skin tone and gender. Currently, up to 2% of the global population is affected by AA [119] with a higher occurrence rate in females, especially in patients with late-onset disease as of age greater than 50 years [120].

Several studies have identified potential polymorphisms associated with AA [121]. Furthermore, several potential triggers have been identified including viral infections such as hepatitis B, C, and swine flu [122], vaccines for influenza, hepatitis, and coronavirus, [123, 124] and other factors such as stress and anxiety [125]. It has been showed that a lack of VDRs may adversely affect epidermal differentiation and hair follicles. Previous studies have also supported a correlation between lower levels of serum vitamin D, zinc, and folate levels in patients with AA when compared to controls [76, 126, 127].

Vitamin D has been employed to treat AA [128]. According to the early work of Xie et al. [129], a decrease in the expression of VDRs in hair follicles has led to active AA patches. In a recent research work by Dasankunju et al. [75] employing 30 AA patients and 30 age-and sex-matched controls, the mean serum vitamin D level detected was 30.2 ng/mL and 38.4 ng/mL, in cases and controls respectively. Vitamin D insufficiency/deficiency was found in 16 patients (53.3%) and a statistically significant relation was observed between serum vitamin D and AA. However, no significant relation was found between serum vitamin D levels and the gender, age, duration of the disease, occupation, number of alopecia lesions, or clinical types of AA [75].

Narang and co-workers [130] conducted a study using 22 adults with limited patchy AA. The observed total hair regrowth was 9% at 12 weeks, and ratio of severity of alopecia tool (SALT50) could be achieved in 46.2% (6/22). In another study by Çerman and co-workers [131], 48 patients with mild and moderate AA who failed topical steroids, displayed a total hair regrowth of 27.1% (13/36) at 12 weeks after undergoing calcipotriol monotherapy. Successful treatments have been reported combining calcipotriol with potent corticosteroids such as mometasone, and clobetasol compared to their monotherapeutic efforts [132, 133].

Treatment methods for AA also involve the use of intralesional vitamin D. In a recent study by Rashad and co-workers, injection of intralesional vitamin D (1 mL, 2.5 mg/mL) for 60 patients with patchy AA every 04 weeks for up to 03 sessions resulted in a hair regrowth score of 4 in 53% (n = 16). This was in comparison to 0% in patients treated with saline injection controls [134]. However, several side effects were reported including pinpoint bleeding, pain, and vasovagal attack in vitamin D treated patients than controls. Several studies summarized in Table 2 used vitamin D analogs as therapeutic agents against other dermatoses. Various vitamin D derivatives including calcitriol, calcipotriol, tacalcitol, maxacalcitol, and hexafluoro-1,25(OH)₂D have been widely employed in treating skin diseases listed in Table 2.