Vitamin D-Mediated Immunoregulation in Degenerative Diseases: Insights into Cardiovascular, Neurodegenerative and Musculoskeletal Disorders.

Degenerative diseases are characterized by the gradual loss of cellular integrity, tissue function, and regenerative capacity. Cardiovascular diseases, neurodegenerative disorders, and musculoskeletal deterioration are considered major categories of degenerative diseases, and vitamin D deficiency has been linked with an increased risk of these conditions. Vitamin D has the potential to modulate neurogenerative process by influencing the progression of neuronal survival, neurogenesis, and synaptic plasticity through both genomic and non-genomic mechanisms mediated by vitamin D receptors, which are widely distributed across brain regions and cell types. Additionally, vitamin D regulates brain immunometabolism by modulating microglial and astrocytic inflammatory responses and oxidative stress. Vitamin D has long been recognized as essential for bone health. Beyond its classical role, vitamin D contributes to the maintenance of bone-muscle homeostasis, enhances mitochondrial biogenesis and ATP production while reducing oxidative stress, and facilitates bidirectional bone-muscle crosstalk through myokines and osteokines to coordinate bone remodeling and muscle regeneration. However, despite these mechanistic insights, the beneficial effects of vitamin D on these diseases-such as reduced risk or mitigation of progression-remains inconclusive. This review explores the relationships between vitamin D and cardiovascular, neurodegenerative, and musculoskeletal diseases, with a focus on the underlying immunological and metabolic mechanisms of actions.