The process of poly(ADP-ribosyl)ation and the major enzyme that catalyses this reaction, poly(ADP-ribose) polymerase 1 (PARP1), were discovered more than 50 years ago. Since then, advances in our understanding of the roles of PARP1 in cellular processes such as DNA repair, gene transcription and cell death have allowed the investigation of therapeutic PARP inhibition for a variety of diseases — particularly cancers in which defects in DNA repair pathways make tumour cells highly sensitive to the inhibition of PARP activity. Efforts to identify and evaluate potent PARP inhibitors have so far led to the regulatory approval of four PARP inhibitors for the treatment of several types of cancer, and PARP inhibitors have also shown therapeutic potential in treating non-oncological diseases. This Review provides a timeline of PARP biology and medicinal chemistry, summarizes the pathophysiological processes in which PARP plays a role and highlights key opportunities and challenges in the field, such as counteracting PARP inhibitor resistance during cancer therapy and repurposing PARP inhibitors for the treatment of non-oncological diseases.

聚（ADP-核糖基）化过程和催化该反应的主要酶聚（ADP-核糖）聚合酶 1 (PARP1) 是在 50 多年前发现的。从那时起，我们对 PARP1 在 DNA 修复、基因转录和细胞死亡等细胞过程中的作用的理解取得了进展，从而可以研究对多种疾病的治疗性 PARP 抑制——尤其是 DNA 修复途径缺陷导致肿瘤的癌症细胞对 PARP 活性的抑制高度敏感。迄今为止，鉴定和评估有效 PARP 抑制剂的努力已导致监管部门批准四种 PARP 抑制剂用于治疗多种类型的癌症，并且 PARP 抑制剂在治疗非肿瘤疾病方面也显示出治疗潜力。