Taxol has been widely used as a first-line chemotherapeutic agent for the treatment of advanced nasopharyngeal carcinoma (NPC). However, acquired drug resistance has caused great difficulties in clinical treatment. Pyroptosis is a newly discovered programmed cell death pathway, and Caspase-1 and gasdermin D (GSDMD) play key roles in driving canonical pyroptosis. Increasing evidence suggests that pyroptosis is associated with the development of cancer; however, the function and mechanism of pyroptosis in NPC remain obscure. In this study, we observed that Taxol treatment caused pyroptotic cell death, along with activation of Caspase-1 and maturation of IL-1β, as well as cleavage of GSDMD, which is the canonical pyroptosis executor. Furthermore, Taxol-induced pyroptotic cell death could be suppressed by Caspase-1 inhibitor (Z-YVAD-FMK) and GSDMD knockout. Moreover, NPC parental cells demonstrated higher levels of pyroptosis than Taxol-resistant cells, and pyroptosis mediated by Caspase-1/GSDMD suppression induced by a Caspase-1 inhibitor and GSDMD knockout could induce a Taxol-resistant phenotype in vitro and in vivo. By transfecting an siRNA targeting Beclin-1 into NPC Taxol-resistant cells, we discovered that autophagy could negatively regulate pyroptosis by inhibiting Caspase-1/GSDMD activation. Taken together, our results indicated that Caspase-1/GSDMD mediated Taxol-induced pyroptosis and a Taxol-resistant phenotype in NPC cell lines, which may be regulated by autophagy. Thus, we provide novel insight into the mechanisms of Taxol-induced cell death and a promising approach to improve the therapeutic outcomes of patients with advanced NPC.

紫杉醇已被广泛用作治疗晚期鼻咽癌 (NPC) 的一线化疗药物。然而，获得性耐药给临床治疗带来了很大的困难。Pyroptosis 是一种新发现的程序性细胞死亡途径，Caspase-1 和 gasdermin D (GSDMD) 在驱动典型的细胞凋亡中起着关键作用。越来越多的证据表明细胞焦亡与癌症的发展有关。然而，NPC 中细胞焦亡的功能和机制仍不清楚。在本研究中，我们观察到紫杉醇处理导致细胞焦亡，同时 Caspase-1 激活和 IL-1β 成熟，以及 GSDMD 裂解，GSDMD 是典型的焦亡执行者。此外，紫杉醇诱导的细胞焦亡可以通过 Caspase-1 抑制剂（Z-YVAD-FMK）和 GSDMD 敲除来抑制。此外，NPC亲本细胞比紫杉醇抗性细胞表现出更高水平的焦亡，并且由Caspase-1抑制剂和GSDMD敲除诱导的Caspase-1/GSDMD抑制介导的焦亡可以在体外和体内诱导紫杉醇抗性表型。通过将靶向 Beclin-1 的 siRNA 转染到 NPC 紫杉醇抗性细胞中，我们发现自噬可以通过抑制 Caspase-1 / GSDMD 激活来负调节细胞焦亡。总之，我们的结果表明 Caspase-1 / GSDMD 介导了紫杉醇诱导的细胞焦亡和 NPC 细胞系中的紫杉醇抗性表型，这可能受自噬调节。因此，