Rong Juan, Han Chenxia, Huang Yan, Wang Yiqin, Qiu Qi, Wang Manjiangcuo, Wang Shisheng, Wang Rui, Yang Juqin, Li Xia, Hu Chenggong, Chen Zhiyao, Deng Lihui, Huang Wei, Xia Qing, Du Dan
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.
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.
Acta Pharm Sin B. 2024 Aug;14(8):3591-3604. doi: 10.1016/j.apsb.2024.04.019. Epub 2024 Apr 24.
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 and pancreatic damage at different doses and treatment time points. Moreover, we observed that conditional overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of C-glucose to C-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-1-mediated LDHA and NLRP3 signaling pathways.
急性胰腺炎（AP）是一种潜在致命性疾病，目前尚无针对性的治疗方法。尽管在多个实验模型和临床试验中对抑制黄嘌呤氧化酶（XO）治疗AP进行了研究，但XO是否为AP的治疗靶点及其主要作用机制仍不清楚。在此，我们旨在重新评估XO是否是加重AP的靶点，而不仅仅是产生引发AP的活性氧。我们首先发现，在坏死性AP模型的血清和胰腺中，XO表达和酶活性显著升高。我们还发现，别嘌醇和非布司他分别作为嘌呤类和非嘌呤类XO抑制剂，在不同剂量和治疗时间点对胰腺腺泡细胞死亡和胰腺损伤均表现出保护作用。此外，我们观察到条件性过表达会加重胰腺坏死和严重程度。进一步的机制分析表明，抑制XO可恢复缺氧诱导因子1α（HIF-1）调控的乳酸脱氢酶A（LDHA）和含NOD样受体家族吡咯结构域3（NLRP3）的信号通路，并减少C-葡萄糖向C-乳酸的转化。最后，我们观察到重症患者临床循环中的XO活性显著升高，且与C反应蛋白水平相关，而重症AP患者胰腺中的XO和尿酸水平也升高。这些结果共同表明，适当抑制XO可能是一种有前景的治疗策略，通过下调HIF-1介导的LDHA和NLRP3信号通路来减轻胰腺坏死并防止重症AP进展。
