PARP抑制剂为携带同源重组修复（HRR）基因突变的晚期前列腺癌（PCa）患者的治疗方法带来了革命。然而，PARP抑制剂在DNA损伤修复途径之外的分子机制仍然不明，寻找在PCa中对PARP抑制剂有良好反应的新的预测性靶点仍然是一个活跃的研究领域。通过西方印迹法测定了PCa细胞系和人类PCa样本中GSDME的表达情况。采用靶向亚硫酸盐测序、基因富集分析（GSEA）、克隆形成、稳定转染细胞系的构建、乳酸脱氢酶（LDH）测定、西方印迹法以及皮下异种移植的小鼠模型等方法来研究GSDME在PCa中的作用。采用体外和体内实验确定olaparib和decitabine的联合治疗效果。我们发现PCa中GSDME的表达较低。有趣的是，我们证明了在经olaparib处理的细胞中，GSDME活性被强烈诱导，并且GSDME启动子的高甲基化抑制了其在PCa细胞中的活性。有趣的是，遗传上过表达GSDME并不抑制肿瘤细胞的增殖，而是使其对olaparib具有敏感性。此外，olaparib和decitabine的药理治疗联合诱导GSDME的表达和通过caspase-3激活产生裂解产物，从而促进细胞噬菌体形成并增强抗肿瘤反应，最终导致肿瘤缓解。我们的研究结果突出了一种在HRR缺陷肿瘤之外增强olaparib长期反应的新的治疗策略，强调了GSDME在调节肿瘤发生中的关键作用。© 2023. Springer Nature Switzerland AG.

PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research.The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments.We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission.Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.© 2023. Springer Nature Switzerland AG.