Addressing the "Nitric Oxide Crisis" in Cardiovascular-Kidney-Metabolic Syndrome: Therapeutic Potential of the Inorganic Nitrate-Nitrite-NO Pathway.

Cardiovascular-kidney-metabolic (CKM) syndrome is a complex interaction of cardiovascular diseases, chronic kidney disease (CKD), and metabolic disorders, with its global prevalence rising due to increasing obesity and metabolic risk factors. The convergence of these conditions significantly worsens patient outcomes, leading to higher morbidity and mortality rates. Key pathophysiological mechanisms underpinning CKM syndrome include insulin resistance, oxidative stress, inflammation, and vascular dysfunction, all of which are exacerbated by reduced nitric oxide (NO) bioavailability and associated signaling dysfunctions. In clinical practice, organic nitrate has been used as NO donors; however, issues such as tolerance, side effects, and endothelial damage limit their effectiveness. The inorganic nitrate-nitrite-NO pathway offers a promising alternative, as emerging evidence from animal and human studies suggests that enhancing this pathway can significantly improve the progression of metabolic disorders, cardiovascular diseases, and CKD. The potential mechanisms may lie in its ability to improve the core pathophysiological processes of CKM syndrome, including inflammation, oxidative stress, insulin resistance, and vascular dysfunction. This review synthesizes current preclinical and clinical studies, highlighting the effects of inorganic nitrate and nitrite in managing CKM syndrome and suggesting avenues for future exploration.