Redox coupling of lactate and β-hydroxybutyrate: An inter-organ circuit linking metabolic flexibility, mitochondrial...

Lactate and β-hydroxybutyrate (βHB), once regarded mainly as metabolic byproducts or alternative fuels, are now increasingly recognized as redox-active metabolites that regulate energy partitioning, mitochondrial function, and adaptive stress responses. Here, we propose a unifying framework in which lactate and βHB form a redox-coupled inter-organ circuit linking the liver, kidney, heart, and skeletal muscle. Through coordinated LDH- and BDH1-dependent reactions and monocarboxylate transport, the lactate-βHB axis integrates carbohydrate and lipid metabolism, supports dynamic fuel switching, and links distinct cytosolic and mitochondrial NAD⁺/NADH redox states during fasting, exercise, hypoxia, and metabolic stress. Disruption of this circuit contributes to mitochondrial dysfunction, impaired metabolic flexibility, and maladaptive redox signaling in disorders including metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. Beyond their bioenergetic roles, lactate and βHB also act as signaling metabolites that influence transcriptional, epigenetic, post-translational, and stress-response pathways, including protein lysine lactylation and β-hydroxybutyrylation, thereby linking metabolic state to cellular adaptation, tissue resilience, and long-term remodeling. Importantly, interventions including exercise, ketogenic or low-carbohydrate diets, SGLT2 inhibition, ketone-based strategies, and NAD⁺-enhancing approaches may help restore lactate-βHB coupling and improve redox homeostasis. This framework positions the lactate-βHB axis as a systems-level mechanism of inter-organ redox communication and provides a redox-biological basis for therapeutic targeting in metabolic and degenerative disease.