Guo Xiaoqi, Han Tianci, Zhang Liang
Liaoning University of Traditional Chinese Medicine, Shenyang 110847, Liaoning, China.
Thoracic Surgery, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning, China.
Crit Rev Eukaryot Gene Expr. 2025;35(5):39-51. doi: 10.1615/CritRevEukaryotGeneExpr.2025058526.
Inducing ferroptosis has become a means of hindering lung cancer progression. Curcumin regulates ferroptosis and participates in lung cancer progression, yet its mechanism on ferroptosis remains unclear. Semaphorin-6A attenuates lung cancer cell migration through the nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase-1 gene (HMOX1) axis. Therefore, the study investigated the mechanism of curcumin inhibiting the malignant progression of lung cancer cells by regulating ferroptosis via the NRF2/HMOX1 pathway. A549 and H209 cell viability, proliferation, death, invasion and migration were assessed by CCK-8, colony formation, lactate dehydrogenase, and Transwell assays. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and Fe2+, glutathione peroxidase 4 (GPX4), nuclear NRF2, and HMOX1, and NRF2 nuclear translocation were measured by kits, Western blot and immunofluorescence. Cell viability, proliferation, invasion and migration were decreased after curcumin treatment, while cell death was significantly increased (all P < 0.01). Curcumin-treated cells showed elevated ROS, MDA and Fe2+ levels, decreased SOD, GSH and GPX4 levels (all P < 0.01), and increased nuclear NRF2 level and nuclear translocation, and HMOX1 expression (all P < 0.01), suggesting that curcumin activated the NRF2/HMOX1 pathway to promote ferroptosis, thereby inhibiting lung cancer cell malignant progression. Liproxstatin-1 or ML385 treatment reversed curcumin-induced anti-tumor effect and ferroptosis. Curcumin activates the NRF2/HMOX1 pathway to promote ferroptosis, thus repressing the malignant progression of lung cancer cells. These findings provide new insights into the mechanism of curcumin's anti-tumor effect and highlight its potential as a therapeutic drug for lung cancer.
诱导铁死亡已成为阻碍肺癌进展的一种手段。姜黄素调节铁死亡并参与肺癌进展，但其对铁死亡的作用机制尚不清楚。信号素-6A通过核因子红细胞2相关因子2（NRF2）/血红素加氧酶-1基因（HMOX1）轴减弱肺癌细胞迁移。因此，本研究探讨了姜黄素通过NRF2/HMOX1途径调节铁死亡来抑制肺癌细胞恶性进展的机制。通过CCK-8、集落形成、乳酸脱氢酶和Transwell实验评估A549和H209细胞的活力、增殖、死亡、侵袭和迁移。通过试剂盒、蛋白质免疫印迹和免疫荧光法检测活性氧（ROS）、丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、Fe2+、谷胱甘肽过氧化物酶4（GPX4）、核NRF2、HMOX1的水平以及NRF2的核转位情况。姜黄素处理后，细胞活力、增殖、侵袭和迁移能力降低，而细胞死亡显著增加（均P<0.01）。姜黄素处理的细胞中ROS、MDA和Fe2+水平升高，SOD、GSH和GPX4水平降低（均P<0.01），核NRF2水平及核转位增加，HMOX1表达增加（均P<0.01），表明姜黄素激活NRF2/HMOX1途径以促进铁死亡，从而抑制肺癌细胞的恶性进展。利普罗他汀-1或ML385处理可逆转姜黄素诱导的抗肿瘤作用和铁死亡。姜黄素激活NRF2/HMOX1途径以促进铁死亡，从而抑制肺癌细胞的恶性进展。这些发现为姜黄素抗肿瘤作用机制提供了新的见解，并突出了其作为肺癌治疗药物的潜力。
