Chen Lin, Wang Zhihao, Zhang Yuyan, Zhu Qingtian, Lu Guotao, Dong Xiaowu, Pan Jiajia, Wu Keyan, Gong Weijuan, Xiao Weiming, Ding Yanbing, Zhang Yanyan, Wang Yaodong
Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, China.
Department of Intensive Care, Key Laboratory of Critical Care Medicine of Yangzhou, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, China.
Inflammation. 2024 Oct 29. doi: 10.1007/s10753-024-02173-5.
Damage to pancreatic acinar cells (PAC) and intracellular metabolic disturbances play crucial roles in pancreatic necrosis during acute pancreatitis (AP). Phosphoglycerate kinase 1 (PGK1) is a crucial catalytic enzyme in glycolysis. However, the impact of PGK1-involving glycolysis in regulating metabolic necrosis in AP is unclear. Transcriptome analysis of pancreatic tissues revealed significant changes in the glycolysis pathway and PGK1 which positively correlated with the inflammatory response and oxidative stress injury in AP mice. Furthermore, we observed a substantial increase in PGK1 expression in damaged PAC, positively correlating with PAC necrosis. Treatment with NG52, a specific PGK1 inhibitor, ameliorated pancreatic necrosis, inflammatory damage, and oxidative stress. Transcriptomic data before and after NG52 treatment along with the Programmed Cell Death database confirmed that NG52 protected against PAC damage by rescuing impaired autophagy in AP. Additionally, the protective effect of NG52 was validated following pancreatic duct ligation. These findings underscore the involvement of PGK1 in AP pathogenesis, highlighting that PGK1 inhibition can mitigate AP-induced pancreatic necrosis, attenuate inflammatory and oxidative stress injury, and rescue impaired autophagy. Thus, the study findings suggest a promising interventional target for pancreatic necrosis, offering novel strategies for therapeutic approaches to clinical AP.
胰腺腺泡细胞（PAC）损伤和细胞内代谢紊乱在急性胰腺炎（AP）期间的胰腺坏死中起关键作用。磷酸甘油酸激酶1（PGK1）是糖酵解中的一种关键催化酶。然而，AP中涉及PGK1的糖酵解在调节代谢性坏死中的作用尚不清楚。胰腺组织的转录组分析显示糖酵解途径和PGK1有显著变化，这与AP小鼠的炎症反应和氧化应激损伤呈正相关。此外，我们观察到受损PAC中PGK1表达大幅增加，与PAC坏死呈正相关。用特异性PGK1抑制剂NG52治疗可改善胰腺坏死、炎症损伤和氧化应激。NG52治疗前后的转录组数据以及程序性细胞死亡数据库证实，NG52通过挽救AP中受损的自噬来保护PAC免受损伤。此外，在胰管结扎后，NG52的保护作用得到了验证。这些发现强调了PGK1参与AP发病机制，表明抑制PGK1可减轻AP诱导的胰腺坏死，减轻炎症和氧化应激损伤，并挽救受损的自噬。因此，研究结果提示了一个有前景的胰腺坏死干预靶点，为临床AP的治疗方法提供了新策略。
