The Ketogenic Diet Through a Metabolomic Lens: Biochemical Pathways, Therapeutic Applications, and Analytical Challenges

Background: The ketogenic diet (KD), a high-fat and low-carbohydrate dietary approach, has been used therapeutically in drug-resistant epilepsy and other neurological and metabolic disorders. Recent interest has shifted toward understanding its broader metabolic effects through metabolomics. This review aims to summarize current knowledge on the biochemical mechanisms and therapeutic implications of the KD, with a particular focus on metabolomic profiling and neurological health. Methods: This narrative review synthesizes findings from the last five years of metabolomic studies investigating the biochemical consequences of the KD and its variants, including the classical KD, modified Atkins diet (MAD), medium-chain triglyceride diet (MCT), and low glycemic index treatment (LGIT). The review integrates data on analytical techniques, such as liquid chromatography–mass spectrometry (LC-MS) and gas chromatography–mass spectrometry (GC-MS), and evaluates alterations in key metabolic pathways. Results: The KD significantly modulates energy metabolism, shifting adenosine triphosphate (ATP) production from glycolysis to fatty acid oxidation and ketone body utilization. It affects mitochondrial function, one-carbon metabolism, redox balance, neurotransmitter regulation, and gut–brain axis signaling. Metabolomic profiling has identified β-hydroxybutyrate (βHB) as a key regulatory metabolite influencing mitochondrial respiration. Long-term KD use may impact renal and hepatic function, necessitating clinical caution and individualized nutritional monitoring. Conclusions: Metabolomic analysis provides critical insights into the multifaceted effects of the KD, supporting its role as a targeted metabolic therapy in neurological diseases. However, potential risks linked to prolonged ketosis warrant further investigation. Future studies should focus on personalized applications and long-term safety profiles of KD variants across patient populations.