奥沙利铂在结直肠癌（CRC）化疗中被广泛应用，但其敏感性已成为限制疗效的主要障碍。许多文献报道Nrf2的活化促进了肿瘤化疗抗药性。本研究探讨了Nrf2抑制在奥沙利铂基于CRC的化疗敏感性中的作用和机制。在体外实验中，我们使用4-辛基琥珀酸（4-OI）激活Nrf2，并使用慢病毒在CRC细胞系中敲低Nrf2。通过测定细胞存活率、克隆形成、凋亡、活性氧物质产生和蛋白免疫印迹法，我们发现奥沙利铂和洛巴铂以剂量依赖的方式抑制HCT-116和LOVO细胞的生长，并促进Nrf2的表达。Nrf2激活剂4-OI降低了CRC细胞对奥沙利铂和洛巴铂的敏感性，而Nrf2敲低提高了CRC细胞对奥沙利铂和洛巴铂的敏感性。通过公共数据库，我们发现在CRC中，正常组织中GPX4的表达较低，而高GPX4表达预示着不良预后。同时，我们发现奥沙利铂在体外降低GPX4的表达。Nrf2敲低增强了奥沙利铂对GPX4和GSH含量的抑制作用，并增加了MDA含量，从而增强了奥沙利铂诱导的铁死亡。随后，我们发现奥沙利铂促进了GSDME-N的表达，并诱导了LDH、IL-1β和TNF-a的释放，而Nrf2敲低加重了GSDME介导的火焰菌素作用的发生。最后，我们发现Nrf2敲低增强了奥沙利铂对HCT116异种移植瘤生长的抑制作用。因此，我们的研究表明，Nrf2抑制通过促进铁死亡和火焰菌素死亡改善了CRC细胞对奥沙利铂的敏感性，为克服CRC化疗抗药性提供了新的靶点。© 2023. Springer Nature Limited.

Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1β, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.© 2023. Springer Nature Limited.