PARP-1促肝纤维化作用及其抑制剂应用前景

The Pro-hepatic Fibrosis Properties of PARP-1 and the Potential Application of Its Inhibitors

肝纤维化(HF)是慢性肝损害的重要病理过程,若广泛的肝内细胞DNA持续损伤和结缔组织增生可形成肝硬化,最终导致器官功能衰竭,癌变甚至死亡。由于聚腺苷二磷酸核糖聚合酶系统[Poly(ADP-ribose)polymerase,PARPs]在肝内细胞DNA损伤与修复中具有重要意义(尤其是PARP-1)。于此,该文通过对PARP-1基因的结构与功能分析,发现其在肝内细胞DNA损伤与修复中,可通过NAD+及能量代谢调节线粒体稳态、调控炎症信号通路NF-κB、激活转录激活蛋白1(AP-1)和抑制AMPK-mTOR通路,进而促进HF,表明PARP抑制剂(PARPI)在抗HF中具有良好的研究与应用价值。

Hepatic fibrosis(HF)is a leading pathological process of chronic liver injury.Extensive cells necrosis in hepatic DNA and connective tissue hyperplasia can induce cirrhosis,eventually leading to organ failure,cancer proliferation or even death.Poly(ADP-ribose)polymerase(PARPs)are key enzymes implicated in hepatocyte DNA repair processes(especially PARP-1).In this paper,through the structural and functional analysis of PARP-1 gene,it was found that it can regulate mitochondrial homeostasis,modulate NF-κB inflammatory signaling pathway,activate transcriptional activator protein 1(AP-1),and inhibit AMPK-mTOR pathway through NAD+and energy metabolism in cellular DNA injury and repair in hepatic cells,thereby promoting HF.This suggests that PARP inhibition(PAPRI)is a promising therapeutic strategy in anti-HF.