Mechanism of Curcumin Inhibition of Malignant Progression of Lung Cancer Cells by Regulating Ferroptosis via the NRF2/HMOX1 Pathway.

Abstract

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.