Recently, a research paper entitled “The hepatic clock synergizes with HIF-1α to regulate nucleotide availability during liver damage repair” has been published by Minxian Qian/Zhongyuan Wang team from School of Life Science and Technology in Nature Metabolism (IF 18.9), a leading international journal. Minxian Qian, Zhongyuan Wang, and Prof. Baohua Liu of Shenzhen University were the co-corresponding authors, and China Pharmaceutical University was the first corresponding organization. Linyuan Peng (PhD student, class of 2021) and Siliang Xiang (PhD student, class of 2023) are the co-first authors of the paper.
Biorhythm clocks control important life processes in cells, including cell cycle, DNA repair, energy metabolism, etc., and are closely related to aging. The mechanism of adaptive regulation of nucleotide content as the body responds to tissue damage and repair is unknown. This study reveals that the internal biological clock of the liver controls the rhythmic fluctuations of the Pentose Phosphate Pathway (PPP) and adjusts the PPP activity to meet the demand for ab initio synthesis of nucleotides during liver injury repair. Experimental analyses using metabolomic, metabolic flow, and organoid analyses confirmed that the pentose phosphate pathway (PPP), but not glycolysis, is required for liver regeneration. Interestingly, intermittent fasting followed by hepatectomy significantly elevated intrahepatic G6PD expression in hepatocytes regeneration of the liver was significantly enhanced, suggesting that preoperative intermittent fasting may contribute to liver recovery after hepatectomy in patients with liver tumors.
Given that the PPP metabolites NADPH and ribose 5-phosphate are important raw materials for antioxidant and nucleotide synthesis, respectively, systemic BMAL1 knockout mice exhibited genomic instability and premature aging symptoms. It was shown that dysregulated nucleotide content led to impaired liver regeneration, DNA damage accumulation and cellular senescence in BMAL1 knockout mice. The unrepaired DNA activated the intracellular cGAS-STING signaling pathway, inducing a senescence-associated secretory phenotype and inflammatory infiltration. This study highlights the critical role of the biological rhythm clock in promoting tissue regeneration and mitigating chronic diseases associated with aging, providing new targets and therapeutic strategies to combat age-related diseases.
The team focuses on the mechanistic study of aging and age-related chronic diseases, and explores disease intervention strategies that target the removal of senescent cells. Since joining CCPC in 2021, the research results have been published in top and above journals in the disciplines of Nature Metabolism (2025), Cell Reports (2024a, 2024b), Redox Biology (2024), etc., which provide new targets for intervention and new ideas for prevention and treatment of age-related chronic diseases.
This work has been supported by the National Natural Science Foundation of China (No. 82022025), the National Key Research and Development Program of China (2022YFC2303200, 2023YFA1801900), the National Natural Science Foundation of China (No. 91949124, 82271602, 32071259), the Jiangsu Shuangchuang Team (2023), and the Multi-targeted Natural Resources Team (2023), and the State Key Laboratory of Multi-target Natural Medicines Grant Program (SKLNMZZ2024JS39).
