Challenges and knowledge gaps in sex differences in cardio–kidney–metabolic syndrome across the lifespan

Abstract Cardiovascular–kidney–metabolic (CKM) syndrome represents a continuum of interrelated adiposity, insulin resistance, cardiovascular disease, kidney dysfunction, and metabolic disturbances that evolve across the lifespan. Emerging evidence demonstrates that both biological sex and sociocultural gender significantly shape CKM risk, progression, and clinical expression. CKM syndrome pathogenesis reflects complex multisystem interactions involving adipose tissue dysfunction, neurohormonal activation, inflammatory signaling, and vascular impairment, all of which exhibit important sex-specific patterns. This review examines CKM syndrome from a sex- and gender-informed perspective, highlighting how endogenous and exogenous sex hormones, reproductive transitions, pregnancy-related complications, and dietary exposures shape the long-term CKM syndrome risk. Particular attention is given to the roles of estrogen and testosterone in modulating adipose biology, vascular function, and metabolic regulation. Polycystic ovary syndrome is discussed as a model of androgen excess and multisystem metabolic vulnerability that accelerates CKM features. Finally, we address brain vulnerability within CKM syndrome, emphasizing shared inflammatory, vascular, and neuroendocrine mechanisms linking metabolic dysfunction to cognitive decline and neuropsychiatric disorders. Recognizing these interconnected and sex-specific influences is critical for advancing precision prevention and treatment strategies across the CKM syndrome spectrum. Graphical abstract