Glucocorticoid resistance-induced inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome pathophysiology.

Prolonged activation of the hypothalamic-pituitary-adrenal axis results in excessive secretion of the glucocorticoid (GC) hormone cortisol, which contributes to weight gain, increased appetite, and inflammation. GCs are essential in regulating stress responses and suppressing immune functions. They bind to the GC receptor and influence gene expression through transcriptional mechanisms. Sustained elevation of GC levels may lead to GC resistance, thereby contributing to inflammation, adiposity, and insulin resistance, which negatively impact the hepatic, cardiovascular, and renal systems. This condition is referred to as cardiovascular-kidney-metabolic (CKM) syndrome. The notable pathologies associated with GC resistance and CKM syndrome are discussed, with particular emphasis on CKM staging and potential therapeutic strategies for individuals with cardiometabolic dysfunction.