## 5 Vitamin D and Dry Eye Disease  
Vitamin D is a fat-soluble vitamin with the molecular formula C\({}_{28}\)H\({}_{44}\)O (vitamin D2, or ergocalciferol) and C\({}_{27}\)H\({}_{44}\)O (vitamin D3, or cholecalciferol) that can be obtained from animal products, such as fish, oil, and eggs, or synthesized in the skin through exposure to sunlight [12]. It plays an important role in modulating inflammation and immune reactions on the ocular surface, which can be helpful for the alleviation of dry eye signs and symptoms [12; 13; 18]. In an in vitro study using cultured human corneal epithelial cells (HCECs), [PERSON] et al. [18] showed that the treatment of HCECs with vitamin D led to an increased expression of antimicrobial peptides and decreased inflammatory mediators [18]. Vitamin D also facilitates the proliferation and differentiation of corneal epithelial cells; thus, it is important for the maintenance and recovery of corneal epithelial barrier function [91]. Furthermore, the micronutrient is one of the key factors in the modulation of systemic calcium absorption, which is important for secretory function in both the salivary and lacrimal glands [25]. In the human cornea, a specific vitamin D receptor ( VDR) is present in epithelial cells and stroma, and vitamin D can be metabolized to active metabolite calcitriol by the enzyme 1-alpha-hydroxylase [92]. An in vitro study showed that calcitriol attenuated the inflammation and oxidative stress responses in cultured HCECs [93]. An experimental study showed that topical calcitriol decreased corneal inflammation and attenuated the expression of inflammatory mediators, suggesting that vitamin D supplementation may be an effective treatment for DED [94]. [PERSON] et al. [95] demonstrated that serum vitamin D levels had a positive correlation with tear vitamin D levels in healthy human patients, and that the concentration of vitamin D was higher in tears than in the serum [95]. Serum vitamin D concentration was significantly correlated with tear production, stability, and dry eye symptoms [26; 96]. [PERSON] et al. [97] also reported that single nucleotide polymorphisms in the VDR gene may increase the risk of DED, suggesting the possible role of vitamin D deficiency in the pathogenesis of DED [97]. [PERSON] et al. [98] showed that resveratrol can restore the increased oxidative stress and decreased vitamin D level in HCECs in hypertonic conditions by activating VDR expression and Notch signaling [98]. Animal studies revealed that the absence of VDR led to a defect in stem cells, suggesting that vitamin D is also essential for limbal stem cell function and corneal epithelial regeneration [92; 93]. Vitamin D was also shown to be effective in the suppression of ocular surface inflammation and the attenuation of corneal neovascularization and meibomian gland injury in animal experimental studies [99; 100]. Several clinical studies have shown that lower serum vitamin D levels were associated with an increased risk of DED [25; 26; 27; 28; 29; 30; 31; 32]. A meta-analysis conducted in 2020 revealed that patients with DED had lower serum vitamin D concentrations compared to a control group by an average of 4 ng/mL [101]. This study also confirmed that vitamin D deficiency is associated with an increased OSDI score and decreased tear secretion [101]. A recent study demonstrated that vitamin D deficiency (<20 ng/dL) was associated with lower Schirmer scores and TBUT and higher OSDI scores [102]. [PERSON] et al. [103] revealed that type 1 DM in pediatric patients was associated with the deterioration of tear parameters, such as the Schirmer test, corneal staining scores, TBUT, and the tear meniscus height and area measured using anterior segment optical coherence tomography, and that the phenomenon is more marked when accompanied by vitamin D deficiency [103]. [PERSON] et al. [104] reported that vitamin D intake may be associated with decreased MGD prevalence among a Japanese population [104]. Decreased vitamin D levels were also associated with an increased risk of NOP [29; 105].