β‐Hydroxybutyrate Acts as an Exercise Mimetic to Protect the Aging Liver

ABSTRACT Liver aging is characterized by pathological features including lipid deposition, exacerbated chronic inflammation, and increased cell death. Although exercise intervention has been proven effective in delaying liver aging, its fundamental biochemical mechanism remains unclear. This study utilized a naturally aged mouse model and an in vitro cellular senescence system to reveal, for the first time, the cascade mechanism by which β‐hydroxybutyrate (β‐HB), a core protective mediator induced by aerobic exercise, delays liver aging through regulating the macrophage–hepatocyte crosstalk. Within the aging microenvironment, disturbance of mitochondrial homeostasis results in the cytosolic release of mtDNA, which activates the cGAS‐STING signaling pathway and drives macrophage polarization towards the pro‐inflammatory M1 phenotype. M1 macrophages subsequently indirectly induce hepatocyte lipid metabolic dysregulation and initiate PANoptosis. Aerobic exercise stimulates the production of endogenous β‐HB, which protects mitochondrial function, inhibits the activation of the cGAS‐STING pathway in macrophages, facilitates macrophages transformation into the anti‐inflammatory M2 phenotype, and ultimately indirectly ameliorates hepatocyte lipid deposition and PANoptosis. Additionally, exogenous β‐HB administration efficiently mimics the endogenous ketogenic effect of aerobic exercise, restoring mitochondrial homeostasis, mitigating inflammation, and reducing PANoptosis levels in the liver of aged mice. This study elucidates the molecular mechanisms by which exercise‐induced endogenous β‐HB confers hepatoprotection. We establish β‐HB as an exercise mimetic, exerting its protective effects on the aging liver through targeted inhibition of the innate immune hub STING. These findings provide a robust theoretical and experimental foundation for the translational application of β‐HB in clinical nutritional strategies for aging intervention.