Metabolic syndrome is increasingly recognized as a systems-level disorder arising from the coordinated breakdown of peptide-governed metabolic networks that regulate mitochondrial bioenergetics, endocrine signaling, inflammatory tone, and inter-organ communication. Beyond the conventional cluster of central adiposity, insulin resistance, dyslipidemia, and hypertension, metabolic syndrome reflects a deeper collapse in the physiological integrity of incretins, adipokines, myokines, hepatokines, mitochondrial-derived peptides (MDPs), and aging-related regulators such as Klotho. Dysregulation of these interconnected peptide systems precipitates mitochondrial dysfunction, adipose inflammatory remodeling, impaired nutrient sensing, endothelial injury, and accelerated metabolic aging. Current therapeutic strategies largely address downstream metabolic abnormalities but do not correct these foundational defects in peptide signaling and mitochondrial resilience.