Vitamin D has gained increased attention in diverse areas of medical research because of its multifaceted role extending beyond bone mineralization and calcium homeostasis. The vitamin D endocrine system provides a wide range of skeletal and extra-skeletal functions. Low vitamin D levels are believed to contribute to the development and progress of autoimmunity, infectious diseases, diabetes mellitus, cardiometabolic disorders, obesity, cancer, gastrointestinal diseases, intestinal dysbiosis, stroke, dementia, and depression [98,99,100,101,102,103]. Vitamin D, a fat-soluble neuroactive prohormone, is increasingly recognized as not only a marker of overall health but also a necessary neurosteroid and immunomodulator, exerting pleiotropic effects on the neurological system. Vitamin D is mainly synthesized by the skin (~80%) from 7-dihydrocholesterol following ultraviolet B exposure. Vitamin D becomes biologically active in humans after undergoing sequential hydroxylation in the liver to 25(OH)D, which is catalyzed by CYP2R1 and CYP27A1, and then in the kidney to the fully active metabolite 1,25(OH)2D, which is catalyzed by CYP27B1 [104]. In a smaller proportion (~20%), vitamin D can also be obtained through dietary intake. Vitamin D metabolites circulate within the bloodstream, typically bound to the vitamin D binding protein (DBP). Among these metabolites, 25(OH)D is vital and is clinically assessed as an indicator of an individual’s vitamin D level [105]. The concentration of 1,25(OH)2D in the blood is strictly regulated through a feedback mechanism involving 1,25(OH)2D itself, parathyroid hormone, calcium, fibroblast growth factor 23, and various cytokines [106].

Vitamin D and its metabolites have the ability to traverse the BBB, and they exert their effects through both genomic and nongenomic pathways, contributing to their multidirectional extra-skeletal benefits. Genomic responses are typically observable over several hours to days, whereas nongenomic responses trigger the rapid activation of various signaling cascades within 1–2 min and 15–45 min [107]. These actions stimulate the transcription and expression of numerous target genes (regulating 3% of the human genome; i.e., >900 genes) participating in numerous cellular processes related to cardiometabolic functions, immune responses, neuroprotection, antioxidation, maintenance of mitochondrial integrity, and cellular proliferation and differentiation. These actions are facilitated by the direct binding of vitamin D metabolites to a nuclear receptor (i.e., VDR), which forms a heterodimer with the retinoid-X-receptor [99,104,108]. VDR and the enzymes involved in vitamin D hydroxylation are widely expressed in various immune cells and brain tissues, including dendritic cells, macrophages, lymphocytes, cerebral endothelial cells, pericytes, neurons, astrocytes, and microglia distributed throughout the CNS, including areas such as the cortex, limbic regions (amygdale, hippocampus, and hypothalamus), deep gray matter (thalamus, basal ganglia, and nucleus accumbens), and the substantia nigra. This widespread distribution highlights their critical roles in both immunological and neurological functions [99,104,108,109,110]. Furthermore, vitamin D metabolites can elicit rapid nongenomic actions in a paracrine and autocrine manner by modulating the expression of genes through a membrane-associated rapid-response steroid-binding protein (i.e., protein disulfide isomerase A3, PDIA3). This mechanism not only contributes to the classical genomic pathway but also enables cross-talk with various signaling pathways, modulating inflammation, apoptosis, oxidative stress, and phosphorylation of cellular proteins, as well as neuron excitability and other electrophysiological phenomena [111,112]. Notably, the expression of PDIA3 in the brain, particularly in regions critical to neurocognitive function, is orders of magnitude greater than its expression in the liver and kidneys [113]. The molecular mechanisms of vitamin D and its metabolites in genomic and nongenomic pathways across large brain areas provide a foundation for understanding their crucial neuropsychiatric functions. This understanding is supported by accumulating in vivo and in vitro evidence indicating that the neurochemical and physiological actions of vitamin D metabolites involve effects on neuroimmunomodulation, neuronal differentiation, neuronal maturation, cellular proliferation, mitochondrial respiratory chain, redox balance, oxidative phosphorylation, calcium signaling/homeostasis, neurotrophism, cerebral angiogenesis, neural circuitry, neuroprotection, neurogenesis, synaptogenesis, synaptic plasticity, neurotransmission/neurotransmitter regulation, and amyloid clearance [99,100,114,115,116]. The robust biological effects of vitamin D on CNS and PNS cells contribute to the protection of the CNS from inflammation at the cellular level (including the BBB and glia). This protection is achieved through multiple mechanisms including the secretion of cytokines and growth factors, cell signaling, response to oxidative stress, regulation of BBB integrity, and trafficking, as well as the support of myelination, axonal homogeneity in peripheral nerves, and neuronal-cell differentiation [117,118].

The level of vitamin D is influenced by various factors, including the extent of sunlight exposure (related to factors such as latitude, season, sedentary indoor lifestyles, sunscreen use, sun avoidance, clothing habits, and home confinement/quarantine), air pollution, personal factors (such as age, sex, ethnicity, body mass index, skin pigmentation, and medication use), underlying medical comorbidities (such as renal and hepatic insufficiency), and genetic factors (nucleotidic polymorphisms of the genes DBP, NADSYN1/DHCR7, CYP2R1, CYP24A1, and VDR) [108,119,120,121,122,123]. However, modifiable environmental or personal factors, instead of genetic variants, were found to be the main determinants of vitamin D levels [122]. Severe vitamin D deficiency (serum 25(OH)D concentration <30 nmol/L) requires correction. However, most guidelines recommend maintaining serum 25(OH)D concentrations of >50 nmol/L for optimal skeletal health in older populations [124]. However, whether this range is suitable for preserving CNS integrity and neuropsychiatric function remains unclear because both low and excessively high serum vitamin D levels are associated with neurocognitive deficits in an inverse U-shaped manner [113]. Accumulating evidence from clinical, epidemiological, and basic science studies indicates that vitamin D insufficiency is widespread across all age groups and even in healthy populations, irrespective of the geographical location or seasonal variation. Moreover, vitamin D deficiency has been demonstrated to be mechanistically and clinically linked to the pathogenesis of various neurological, psychiatric, and autoimmune disorders, such as cerebrovascular diseases, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, depression, and schizophrenia [98,101,103,104,108,124,125,126,127].

The inconsistent results in clinical interventional studies on the role of vitamin D supplementation in the development or progress of autoimmune and neuropsychiatric diseases can be attributed, in part, to various methodological factors, such as differences in patient cohorts, varied doses of vitamin D administered, different study designs, and bioanalytical determination methods used [108,124,128]. Although vitamin D deficiency is a common risk factor, the origin of these disorders is complex. Whether vitamin D deficiency is a causal factor influencing the etiology of these illnesses or is a consequence of them, coupled with lifestyle changes and reduced sun exposure, remains debatable.

Apart from its recognized benefits for overall systemic health, such as its anti-infection properties, its supporting role in mitochondrial function, cardiometabolic benefits, immunomodulatory effects, and anti-inflammatory effects, vitamin D exerts effects on immunomodulation or anti-inflammation, neuroprotection, regulation of monoamine neurotransmission, preservation of BBB integrity, vasculometabolic functions, modulation of gut microbiota, and enhancement of telomere stability. These multifaceted roles highlight the importance of vitamin D in maintaining normal brain functioning as well as preventing and managing neuropsychiatric, neuroinflammatory, and neurodegenerative disorders.

Vitamin D is a well-known active regulator of both innate and adaptive immunity and plays a crucial role in safeguarding the nervous system against invasive pathogens [129]. Regarding innate immunity, vitamin D enhances the synthesis of antimicrobial peptides such as defensin beta 2 and cathelicidin in macrophages and monocytes. Additionally, it promotes chemotaxis, autophagy, and phagolysosomal fusion in macrophages and natural killer cells. Furthermore, vitamin D reinforces gut microbiota homeostasis and enhances the physical barrier function of intestinal epithelial cells [103,130]. With respect to adaptive immunity, vitamin D promotes an anti-inflammatory state by regulating T cells, B cells, and antigen-presenting cells (dendritic cells and macrophages) through the suppression of the activation of Th1 cells, inhibition of the production of proinflammatory cytokines, and modulation of the activities of Th2 cells, T regulatory cells, and Th17 cells [101,103,130]. Overall, as a tolerogenic, anti-inflammatory cytokine, vitamin D not only aids the immune system in dampening excessive or chronic reactions but also facilitates the rapid and effective elimination of pathogens. The immune regulatory effects induced by vitamin D in peripheral tissues may also extend protection to the CNS by locally reinforcing the BBB and reducing glial activation in the brain parenchyma.

Vitamin D exerts anti-inflammatory effects on human microglia by inhibiting the production of proinflammatory cytokines and facilitating differentiation of M2 macrophages and the upregulation of the anti-inflammatory Toll-like receptor, thus inhibiting inflammation-driven neural injury [123]. Moreover, it serves as a potent antioxidant during inflammatory processes. It achieves this by enhancing defective autophagy and mitochondrial function through the inhibition of the mTOR pathway. Vitamin D also reduces oxidative stress and inflammatory responses by activating FoxO-dependent antioxidant pathways, inhibiting NF-κB signaling, promoting reactive oxygen species-scavenging enzymes, downregulating NADPH oxidase, and upregulating Nrf2 [123]. Vitamin D can be regarded as a pivotal molecule for promoting cell survival. This is achieved by synchronizing calcium oscillatory signaling in cells, regulating autophagy or apoptosis, and critically regulating the inflammasome during stress responses. Additionally, it promotes protein homeostasis and longevity through stress response pathway genes such as skn-1, ire-1, and xbp-1 [131,132]. Furthermore, it downregulates the expression of adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in endothelial cells. This modulation of adhesion molecules influences the BBB by controlling the migration of immune cells to the CNS [117,133]. Collectively, neuroinflammation and oxidative stress play fundamental roles in neural injury, BBB breakdown, and the progression of neurodegenerative processes. These processes are key factors underlying a wide range of neurological, psychiatric, and cardiovascular diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and depression [101,134,135,136], rendering these processes rational targets for new therapies even in individuals with sufficient vitamin D levels.

Vitamin D regulates neuronal differentiation and maturation, enhances neuronal survival, and prevents neurotoxicity through the following mechanisms: (1) promotion of the synthesis of essential neurotrophic factors, such as nerve growth factor, glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and neurotrophins; (2) modulation of neuronal calcium homeostasis through the downregulation of L-type voltage-sensitive calcium channels and synthesis of calcium-binding proteins, such as calbindin, parvalbumin, and calretinin; (3) reduction of inducible nitric oxide synthase and increases in glutathione, superoxide dismutase, and arginase-1, thereby protecting against mitochondrial dysfunction; and (4) enhancement of the synthesis of other neurosteroids such as estrogen and progesterone [112,117,137]. Additionally, it affects synaptic or neuronal plasticity, axiogenesis or axonal growth, neuronal myelination, and the maintenance of the cytoskeleton and cell transport of organelles through the regulation of numerous proteins, such as drebrin, growth-associated protein-43, connexin 43, synapsin-1, neurofilament, tubulin, actin, microtubule-associated protein-2, glial fibrillary acidic protein, creatine kinase b, kinesin, and dynactin [138,139]. Vitamin D may have beneficial effects for neurodegenerative processes associated with Alzheimer’s disease. It can help attenuate the hyperphosphorylation of the tau protein, counteract neuronal death, mitigate amyloid-induced cytotoxicity, and regulate amyloid homeostasis. It achieves this by (1) enhancing the clearance of amyloid plaques through increased phagocytosis by macrophages and facilitating brain-to-blood efflux across the BBB, mediated by low-density lipoprotein receptor related protein-1, and (2) reducing the amyloid production and increasing its degradation by factors such as nicastrin, neprilysin, and secretases [140,141,142,143,144,145]. The consequences of long-term deficiency or inefficient utilization of vitamin D can disrupt these neuroprotective mechanisms, potentially rendering neurons more susceptible to aging and neurodegeneration.

Vitamin D actively regulates the genetic processes responsible for the synthesis of acetylcholine, dopamine, serotonin, and gamma-aminobutyric acid, all of which modulate a broad spectrum of neuropyschological functions, including mood, cognition, learning, memory, reward processing, and sleep [146,147].

The functional and structural integrity of the BBB is crucial for maintaining the homeostasis of the brain microenvironment. This semipermeable membrane is essential for regulating the influx and efflux of biological substances at the brain–blood interface, which is fundamental for supporting the brain’s metabolic activity and neuronal function. Vitamin D has potential benefits for neurovascular coupling and BBB function. Within the neurovascular unit, various enzymes including CYP27A1, CYP27B1, and CYP24A1 are expressed in astrocytes, endothelial cells, microglia, and oligodendrocytes, and CYP27B1 is abundantly expressed in neurons [148]. The VDR is primarily expressed in astrocytes, whereas PDIA3 is abundantly expressed in all cerebral cell types [148]. Brain pericytes lack the expression of CYP27B1 and are therefore unable to synthesize 1,25(OH)D. This observation suggests that pericytes rely on paracrine or circulating 1,25(OH)D to maintain neurovascular function [148]. Brain microvascular endothelial cells have a notable ability to transform cholecalciferol into 25(OH)D. They also express VDR and PDIA3, contributing to the regulation of BBB transporters (e.g., permeability-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein) and tight-junction proteins (e.g., occludin, claudin-5, and zonula occludens-1) [117,148]. Thus, vitamin D may play a vital role in counteracting a deleterious cascade of injury processes and functional deficits that result from compromised BBB integrity.

Vitamin D exerts various systemic cardiovascular effects through VDR-mediated mechanisms in cardiomyocytes and vascular endothelial cells as well as through the regulation of the RAAS, adiposity, energy expenditure, and pancreatic cell activity [149]. In the genomic pathway of cerebral endothelial cells, the expression of genes encoding stromal cell-derived factor 1α, vascular endothelial growth factor, and nitric oxide synthase is upregulated, contributing to vasodilation and anti-inflammation. Insulin-like growth factor 1 is involved in the neuroprotection of axons and dendrites and thrombolysis through the activation of plasminogen. The tight-junction proteins of the BBB ensure microvascular structural integrity and microcirculatory function. Nerve growth factors are also influenced by this genomic pathway [150]. Collectively, these beneficial genomic effects on vascular endothelial cells result in reduction of thrombogenicity, reduction of vasoconstriction, inhibition of oxidative/nitrative stress and atherogenesis, enhancement of endothelial repair, decrease in foam cell formation, and improvement of vascular relaxation and dilatation [151]. Additionally, vitamin D plays a role in regulating matrix homeostasis through the modulation of specific matrix metalloproteinases and tissue inhibitors of metalloproteinases, all of which are critical in major cerebrovascular diseases, including atherosclerosis, arteriosclerosis, and stroke [123]. By combining its vasculometabolic actions with the potent systemic and neural immunomodulatory and antioxidant effects, vitamin D can positively modulate cerebral vascular homeostasis and BBB function and prevent vascular dysfunction and tissue injury as a result of systemic and local (neural) inflammation.

The VDR plays a role in regulating the gut microbiome by suppressing inflammation, maintaining barrier function, promoting microbial homeostasis, and reducing insulin resistance [152,153,154]. More than 90% of the body’s serotonin is synthesized in the gut, predominantly by enterochromaffin cells. Disruption of the intestinal microbiota triggered by inflammatory processes has been shown to directly compromise the synthesis of this monoamine [155]. Vitamin D supplementation has been demonstrated to promote an increase in serum serotonin levels in individuals with depression as well as in serum dopamine levels in children with attention deficit/hyperactivity disorder [155]. Studies have suggested that vitamin D may serve as a key regulator in the gut–brain axis, modulating gut microbiota and alleviating psychiatric symptoms such as depression and anxiety [155,156]. Consequently, vitamin D deficiency leads to dysbiosis, a probable reason for the increased vulnerability to inflammation-mediated illnesses.

Vitamin D has been demonstrated to be involved in telomere biology and genomic stability through various pathways. It has the potential to preserve telomere length, inhibit cellular aging, and mitigate telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms [157]. Significantly low levels of telomerase activity lead to the development of shortened telomeres, which in turn triggers cell cycle arrest, ultimately leading to cell senescence and apoptosis [157].