The AMPK/NRF2/FOXO Axis in CKD—Molecular and Clinical Perspectives

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Abstract
Chronic Kidney Disease (CKD) is a global health crisis, projected to be the fifth leading cause of death by 2040. Its progression is driven by a reinforcing loop of mitochondrial dysfunction, oxidative stress, and chronic inflammation. The AMPK-NRF2–FOXO axis serves as a central “redox-metabolic rheostat” that maintains renal homeostasis but is commonly dysfunctional in CKD. Herein, we explore the molecular crosstalk within this network, where AMPK acts as a metabolic and redox sensor, NRF2 governs the cytoprotective response, and FOXO isoforms regulate autophagy, antioxidative defense, and senescence. We highlight the functional paradoxes within the axis and evaluate the benefits and drawbacks of nutraceuticals and pharmacological agents, such as NRF2 inducer bardoxolone methyl, underscoring the necessity for context-dependent modulation. Furthermore, we examine the AMPK–NRF2–FOXO axis within the current clinical management, according to the 2024/2026 KDIGO guidelines. These guidelines reflect a shift toward a multi-targeted pharmacological approach involving metformin, SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, and hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors.

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