Long non-coding RNA lung cancer-associated transcript 1 regulates ferroptosis via microRNA-34a-5p-mediated GTP cyclohydrolase 1 downregulation in lung cancer cells

Ferroptosis, a recently discovered type of programmed cell death triggered by excessive accumulation of iron-dependent lipid peroxidation, is linked to several malignancies, including non-small cell lung cancer. Long non-coding RNAs (lncRNAs) are involved in ferroptosis; however, data on their role and mechanism in cancer therapy remains limited. Therefore, the aim of the present study was to identify ferroptosis-associated mRNAs and lncRNAs in A549 lung cancer cells treated with RAS-selective lethal 3 (RSL3) and ferrostatin-1 (Fer-1) using RNA sequencing. The results demonstrated that lncRNA lung cancer-associated transcript 1 (LUCAT1) was significantly upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues. Co-expression analysis of differentially expressed mRNAs and lncRNAs suggested that LUCAT1 has a crucial role in ferroptosis. LUCAT1 expression was markedly elevated in A549 cells treated with RSL3, which was prevented by co-incubation with Fer-1. Functionally, overexpression of LUCAT1 facilitated cell proliferation and reduced the occurrence of ferroptosis induced by RSL3 and Erastin, while inhibition of LUCAT1 expression reduced cell proliferation and increased ferroptosis. Mechanistically, downregulation of LUCAT1 resulted in the downregulation of both GTP cyclohydrolase 1 (GCH1) and ferroptosis suppressor protein 1 (FSP1). Furthermore, inhibition of LUCAT1 expression upregulated microRNA (miR)-34a-5p and then downregulated GCH1. These results indicated that inhibition of LUCAT1 expression promoted ferroptosis by modulating the downregulation of GCH1, mediated by miR-34a-5p. Therefore, the combination of knocking down LUCAT1 expression with ferroptosis inducers may be a promising strategy for lung cancer treatment.