HEATR1 promotes cisplatin resistance by inhibiting ferroptosis via p53-SAT1-ALOX15 pathway in non-small cell lung cancer

Abstract Lung cancer is one of the most common cancers around the world, and non-small cell lung cancer (NSCLC) is the major subtype. As a commonly used chemotherapy agent, cisplatin (DDP) resistance remains a challenge in clinical application. Our study was conducted to reveal the mechanism of DDP resistance and provide novel targets for NSCLC treatment. DDP-resistant and non-resistant NSCLC specimens were collected to detect the expression of HEATR1. DDP-resistant and non-resistant NSCLC cells were used for experiments. The effect of HEATR1 on the proliferation, apoptosis, and lipid reactive oxygen species (ROS) was evaluated in DDP-resistant A549 cells. The expression of HEATR1 was significantly higher in DDP-resistant NSCLC tissues and cells compared with non-resistant ones. The expression of p53, SAT1, and ALOX15 was decreased in DDP-resistant cells. The inhibition of HEATR1 significantly reduced the proliferation and promoted the lipid ROS of NSCLC cells via activating ferroptosis and p53-SAT1-ALOX15 pathway in vitro and in vivo, whereas its overexpression exhibited reversed effects. Moreover, the inhibition of p53 and ALOX15 would reverse the oncogenic effects of HEATR1 and inactivate ferroptosis in DDP-resistant NSCLC cells, which indicated the involvement of p53 and ALOX15 in HEATR1-mediated DDP resistance. In conclusion, our study revealed that HEATR1 could promote DDP resistance in NSCLC by inhibiting ferroptosis via the p53-SAT1-ALOX15 pathway. HEATR1 was a potential target for the treatment of DDP-resistant NSCLC. Significance of the study: The present study focus on the role and the potential mechanism of HEATR1 in DDP-resistant non-small cell lung cancer (NSCLC) cells. Our data demonstrated that HEATR1 might promote the proliferation and reduce the lipid ROS of NSCLC cells via activating ferroptosis and p53-SAT1-ALOX15 pathway. The findings revealed the interaction between HEATR1 and p53 in NSCLC, providing putative therapeutic strategies for treatment of DDP-resistant NSCLC.