Modulating hepatic hypoxanthine metabolism relieve metabolic stress-related neurovascular resilience disturbance via the liver-brain axis

BACKGROUND: Unhealthy lifestyles promote brain aging, but their mechanisms remain unclear. The liver-brain axis acts as a key mediator of brain dysfunction and warrants investigation in lifestyle-induced brain aging. PURPOSE: To elucidate how the liver-brain axis mediates lifestyle-triggered neurovascular resilience disturbance and associated brain aging phenotypes, and identify effective anti-aging intervention targets. STUDY DESIGN: A combination of in vivo animal models, multi-omics analyses, computational simulation, brain organoid experiments, and molecular biology techniques to explore the mechanism of liver-brain axis mediates lifestyle-triggered neurovascular resilience disturbance and associated brain aging phenotypes and verify the efficacy of Bazi Bushen capsule (BZBS) intervention. METHODS: A mouse model established using a combined high-fat/high-sugar diet and circadian disruption (HFHS/CD). Cognitive function and anxiety-like behaviors were evaluated. Multi-omics analyses were performed, and liver-brain axis/hypoxanthine signals were verified via computational simulation and brain organoids. Active ingredient targets were identified by molecular docking, drug affinity responsive target stability, and validated by biolayer interferometry. RESULTS: HFHS/CD induced cognitive decline and anxiety accompanied by apparent brain aging-related phenotypes, which were alleviated by nicotinamide mononucleotide (NMN) and BZBS. Dysregulated hepatic hypoxanthine metabolism under metabolic stress contributed to neurovascular homeostasis disturbance, characterized by compromised BBB integrity and excessive microglial activation. In vitro experiments further indicated that elevated hypoxanthine levels were involved in endothelial senescence, potentially through P2X7-dependent suppression of NRF2-governed glutathione metabolism. BZBS acted through multiple targets: imperatorin/isopimpinellin regulated hepatic purine nucleoside phosphorylase (PNP)/hypoxanthine phosphoribosyltransferase 1 (HPRT1) to reduce hypoxanthine, while osthole/schizandrin A maintained endothelial integrity. CONCLUSION: Aberrant hypoxanthine metabolism induced by unhealthy lifestyles may disrupt neurovascular homeostasis through the liver-brain axis and contribute to the occurrence of brain aging phenotypes. BZBS improves age-related brain dysfunction by targeting hypoxanthine metabolism and protecting endothelial function, representing a promising intervention.