Blocking METTL3-mediated lncRNA FENDRR silence reverses cisplatin resistance of lung adenocarcinoma through activating TFRC-mediated ferroptosis pathway.

Targeting ferroptosis pathway becomes a new solution for cisplatin (DDP) resistance in lung adenocarcinoma (LUAD), and further research is required to explore the molecular mechanisms underlying ferroptosis and DDP resistance, providing biotargets for LUAD treatment. In this study, DDP-sensitive A549 cells and DDP-resistant A549/DDP cells were treated with DDP, DDP sensitivity was detected through using CCK-8 method and colony formation assay, ferroptosis-related markers were determined through commercial kits, and the molecular regulatory mechanism was analyzed through methylated RNA immunoprecipitation, RNA pull-down, dual luciferase assay, quantitative real-time polymerase chain reaction and western blotting assay. Results showed that compared to A549 cells, FENDRR was downregulated in A549/DDP cells, and FENDRR increased iron content, labile iron pool, lipid peroxidation, LDH release and ROS levels, accelerating ferroptosis to promote DDP sensitivity. Interestingly, we found that METTL3-mediated N6-methyladenosine modification YTHDF2 dependently resulted in FENDRR degradation, and FENDRR overexpression elevated TFRC expression through sponging miR-761. Mechanistically, METTL3 inhibited the FENDRR/TFRC axis to alleviate DDP-induced ferroptosis, promoting DDP resistance in LUAD cells. Collectively, our findings identify a novel molecular regulatory mechanism in DDP resistance of LUAD, and suggest that FENDRR might be an attractive target for addressing DDP resistance.