The Nrf2-HMOX1 pathway as a therapeutic target for reversing cisplatin resistance in non-small cell lung cancer via inhibiting ferroptosis

Cisplatin resistance is a major cause of poor prognosis in non-small cell lung cancer (NSCLC). Cisplatin-induced lung cancer cell death is associated with ferroptosis, a type of recently identified programmed cell death. Nrf2 is a critical component of the antioxidant system, and its protumorigenic activity in lung cancer has been extensively studied. However, the role of Nrf2 in cisplatin-induced ferroptosis and drug resistance remains elusive. Here, we demonstrated that cisplatin treatment induced ferroptosis in parental A549 lung adenocarcinoma cells and that this effect was significantly reduced in cisplatin-resistant A549/DDP cells. Knocking down Nrf2-sensitized A549/DDP cells to cisplatin-induced cytotoxicity by enhancing ferroptosis. Moreover, we demonstrated that Nrf2 promotes the expression of HMOX1 and that the Nrf2-HMOX1 pathway is critical for mediating its anti-ferroptotic function. Additionally, immunohistochemical analysis of NSCLC specimens revealed that Nrf2 expression was correlated with HMOX1 and high levels of Nrf2 and HMOX1 were associated with poor patient survival. These findings suggest that the HMOX1-Nrf2 pathway significantly influences treatment outcomes in NSCLC. Ultimately, we demonstrated that treatment with the Nrf2 inhibitor ML385 promoted ferroptosis by inhibiting the Nrf2-HMOX1 pathway, restoring cisplatin sensitivity in drug-resistant cells. Our findings provide insights into the mechanism underlying cisplatin resistance and suggest that targeting the Nrf2-HMOX1 pathway enhances cisplatin-induced ferroptosis and improves NSCLC treatment outcomes.