Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis  

作　　者：Juan Rong Chenxia Han Yan Huang Yiqin Wang Qi Qiu Manjiangcuo Wang Shisheng Wang Rui Wang Juqin Yang Xia Li Chenggong Hu Zhiyao Chen Lihui Deng Wei Huang Qing Xi Dan Du 

机构地区：[1]West China Center of Excellence for Pancreatitis,Institute of Integrated Traditional Chinese and Western Medicine,West China Hospital/West China Medical School,Sichuan University,Chengdu 610041,China [2]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [3]Advanced Mass Spectrometry Center,Research Core Facility,Frontiers Science Center for Disease-related Molecular Network,West China Hospital,Sichuan University,Chengdu 610213,China [4]Proteomics-Metabolomics Platform,Research Core Facility,Institutes for Systems Genetics,West China Hospital,Sichuan University,Chengdu 610093,China [5]Biobank,West China Hospital,Sichuan University,Chengdu 610093,China [6]West China School of Nursing,Sichuan University,Chengdu 610041,China [7]Department of Critical Care Medicine,West China Hospital,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3591-3604,共14页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Dan Du,82170905);the Program of Science and Technology Department of Sichuan Province(Dan Du,2023NSFSC1755,China);the State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College(Dan Du,GTZK202107,China);the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Qing Xia,ZYJC18005,China);the West China,Nursing Discipline Development Special Fund Project,Sichuan University(Xia Li,HXHL21060,China).

摘　　要：Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical trials,whether XO is a target of AP and what its the main mechanism of action is remains unclear.Here,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models.We also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points.Moreover,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity.Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like receptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of^(13)C_(6)-glucose to^(13)C_(3)-lactate.Lastly,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP patients.These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

关 键 词：Xanthine oxidase inhibitor Multi-omics HIF-1A Necrotizing acute pancreatitis LACTATE Therapeutic target NLRP3 Metabolic flux 

分 类 号：R965[医药卫生—药理学]