Long noncoding RNA PCAT7 confers radioresistance of esophageal squamous cell carcinoma by promoting GCLM-mediated anti-ferroptosis

Radiotherapy is one of the standard treatments for advanced esophageal squamous cell carcinoma (ESCC), but the prognosis remains poor due to radioresistance of tumor cells. Emerging evidence implicates ferroptosis and long non-coding RNAs (lncRNAs) in the mechanisms of radioresistance. Through bioinformatics analysis, we identified lncRNA PCAT7 as a ferroptosis-associated lncRNA biomarker in ESCC. However, the role and mechanism of PCAT7 in radioresistance and ferroptosis of ESCC remain unclear. Bioinformatics analysis was used to identify PCAT7 as a differentially expressed ferroptosis-related lncRNA in ESCC. Functional validation demonstrated its oncogenic properties through proliferation (CCK-8/colony formation assays), migration (transwell assay), and radioresistance (flow cytometry/xenografts assays), while ROS/MDA quantification and Western blot confirmed its anti-ferroptosis activity. RNA sequencing was conducted to confirm the downstream target genes and signaling pathways mediated by PCAT7. RNA immunoprecipitation assay, actinomycin D RNA stability experiment and rescue experiment were performed to identify the mechanism by which PCAT7 conferred ESCC radioresistance. PCAT7 up-regulation was consistently detected in both ESCC patient specimens and ESCC cell lines. Genetic silencing of PCAT7 attenuated the aggressive phenotype and radiation resistance of ESCC cell lines through ferroptosis activation, as demonstrated in cellular and animal models. Furthermore, PCAT7 could activate the PI3K/AKT signaling pathway by promoting the glutamate-cysteine ligase modifier subunit (GCLM), an anti-ferroptosis protein, thereby facilitating radioresistance of ESCC cells. Moreover, FTO-mediated demethylated N6-methyladenosine participated in the upregulation of PCAT7. PCAT7 inhibited ferroptosis and enhanced radioresistance via GCLM /PI3K/AKT signaling axis in ESCC, a process modulated by FTO-mediated N6-methyadenosine (m6A) demethylation. Our study reveals PCAT7 as a pro-radioresistance lncRNA and potential therapeutic target for enhancing efficiency of radiotherapy.