The AMPK–SIRT1–PGC-1α Axis in Cardiovascular–Kidney–Metabolic Syndrome

The AMPK/SIRT1/PGC-1α axis is a key signaling network involving several metabolic pathways, including mitochondrial biogenesis, macronutrient metabolism, transcriptional control, and adaptive responses to metabolic stress. Dysregulation of this axis may be encountered in the pathogenesis of cardiovascular–kidney–metabolic syndrome, characterized by systemic inflammation, oxidative stress, and impaired mitochondrial metabolism. Under energy-depleted conditions, activated adenosine monophosphate-activated protein kinase (AMPK) leads to increased NAD+ levels, thus promoting the activity of silent information regulator 1 (SIRT1). SIRT1 further contributes to deacetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), hence enhancing its transcriptional activity and promoting mitochondrial biogenesis. In recent years, several therapeutic strategies targeting key modulators of this regulatory pathway have been proposed, offering promising perspectives for the management of this complex syndrome. In this review, we aim to explore the mechanisms underlying cardiovascular–kidney–metabolic syndrome, with a particular interest in the AMPK/SIRT1/PGC-1α signaling axis, regarding its role in the initiation and progression of this systemic disorder.