Abstract
People with Down syndrome represent a highly vulnerable population, frequently showing vitamin D deficiency together with an elevated risk of metabolic and neuromuscular dysfunction. This susceptibility derives from several factors, including muscular hypotonia, excess body weight, thyroid abnormalities, and immune dysregulation. The coexistence of these conditions compromises bone and muscle health, increases cardiometabolic risk, and reduces motor abilities and coordination, thereby predisposing individuals to falls, sarcopenia, sarcopenic obesity, and long-term disability. Vitamin D, traditionally known for its essential role in bone health, is now recognized as a pleiotropic hormone regulating immune responses, metabolic balance, and muscle performance. Its deficiency is increasingly linked to obesity, insulin resistance, diabetes mellitus, dyslipidemia, and metabolic syndrome. These adverse outcomes are mediated through mechanisms involving chronic inflammation, oxidative stress, mitochondrial impairment, and disrupted adipokine signaling. This review integrates current molecular, cellular, and clinical evidence on the multifaceted actions of vitamin D in Down syndrome. Particular emphasis is placed on its effects on insulin signaling, adipose tissue metabolism, inflammatory regulation, and muscle strength. Finally, vitamin D is discussed as a biomarker and therapeutic target to guide personalized interventions aimed at improving metabolic health, maintaining muscle function, and promoting long-term independence in this high-risk population.