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

  • Free Radic Biol Med. 2026 Jul 15:255:160-178. doi: 10.1016/j.freeradbiomed.2026.07.024.
Huifang Tu  1 ,  Yunlong Hou  2 ,  Wenwen Cui  3 ,  Xiaoqing Wang  4 ,  Meng Chen  3 ,  Min Shi  3 ,  Tianyu Kang  5 ,  Yibing Jiang  6 ,  Qiulan Wu  5 ,  Wenyan Li  7 ,  Jingqi Cai  8 ,  Lu Wang  3 ,  Zixuan Wang  3 ,  Bin Hou  3 ,  Liping Chang  3 ,  Shaohua Zhao  9 ,  Zhenhua Jia  10 ,  Mengnan Li  11
Affiliations
  • 1. Chengde Medical University, Anyuan Road, Shuangqiao District, Chengde City, Hebei Province, 067000, China.
  • 2. State Key Laboratory for Innovation and Transformation of Luobing Theory, No. 238 Tianshan Avenue, High - Tech Industrial Development Zone, Shijiazhuang City, Hebei Province, 050035, China; Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang City, Hebei Province, 050017, China; Graduate School, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Qiaoxi District, Shijiazhuang City, Hebei Province, 050091, China.
  • 3. State Key Laboratory for Innovation and Transformation of Luobing Theory, No. 238 Tianshan Avenue, High - Tech Industrial Development Zone, Shijiazhuang City, Hebei Province, 050035, China.
  • 4. Academy of Chinese Medicine Sciences Henan University of Chinese Medicine, No. 156 East Jinshui Road, Zhengdong New District, Zhengzhou City, Henan Province, 450046, China.
  • 5. Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang City, Hebei Province, 050017, China.
  • 6. Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Xiangfang District, Harbin City, Heilongjiang Province, 150040, China.
  • 7. State Key Laboratory for Innovation and Transformation of Luobing Theory, No. 238 Tianshan Avenue, High - Tech Industrial Development Zone, Shijiazhuang City, Hebei Province, 050035, China; Graduate School, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Qiaoxi District, Shijiazhuang City, Hebei Province, 050091, China.
  • 8. Graduate School, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Qiaoxi District, Shijiazhuang City, Hebei Province, 050091, China.
  • 9. Chengde Medical University, Anyuan Road, Shuangqiao District, Chengde City, Hebei Province, 067000, China; State Key Laboratory for Innovation and Transformation of Luobing Theory, No. 238 Tianshan Avenue, High - Tech Industrial Development Zone, Shijiazhuang City, Hebei Province, 050035, China. Electronic address: [email protected].
  • 10. State Key Laboratory for Innovation and Transformation of Luobing Theory, No. 238 Tianshan Avenue, High - Tech Industrial Development Zone, Shijiazhuang City, Hebei Province, 050035, China; Graduate School, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Qiaoxi District, Shijiazhuang City, Hebei Province, 050091, China. Electronic address: [email protected].
  • 11. State Key Laboratory for Innovation and Transformation of Luobing Theory, No. 238 Tianshan Avenue, High - Tech Industrial Development Zone, Shijiazhuang City, Hebei Province, 050035, China; Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang City, Hebei Province, 050017, China. Electronic address: [email protected].
PMID: 42456994 DOI: 10.1016/j.freeradbiomed.2026.07.024
Abstract

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.

Keywords
Blood-brain barrier dysfunction; Hypoxanthine/xanthine metabolism; Liver-brain axis; P2X7-NRF2-glutathione axis; Traditional medicine; Virtual knockout.
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