Circ_GLS/miR-410-3p/GSK3beta/beta-catenin axis modulates malignant phenotypes of non-small cell lung cancer cells via regulation of cell cycle, apoptosis, ferroptosis, and EMT.

Lung cancer, with non-small cell lung cancer (NSCLC) representing 85 % of cases, has high global incidence and mortality. Early detection is challenging, often leading to late-stage diagnosis and missed surgical opportunities, highlighting the need for novel biomarkers and therapeutic targets. CircRNA sequencing identified a novel 643-nt circRNA, circ_GLS, which was significantly downregulated in tumors. Functional assays including CCK-8, colony formation, transwell, and wound healing assays, along with xenograft models, demonstrated that circ_GLS inhibits proliferation, migration, and invasion of NSCLC cells in vitro and in vivo. RNA pull-down with RT-qPCR and dual-luciferase assays confirmed direct binding between circ_GLS and miR-410-3p, and between miR-410-3p and GSK3beta. Rescue experiments involving miR-410-3p and GSK3beta validated the role of the circ_GLS/miR-410-3p/GSK3beta/beta-catenin axis in the malignant phenotype, and further experiments elucidated mechanisms via cell cycle, apoptosis, ferroptosis, and epithelial-mesenchymal transition (EMT) modulation. Clinical and bioinformatic analyses revealed that circ_GLS was significantly downregulated in NSCLC tissues, while miR-410-3p was significantly upregulated and GSK3beta downregulated, correlating with diagnosis and prognosis, though independent validation is needed. In conclusion, this study demonstrates for the first time in NSCLC that this axis regulates malignancy, suggesting their potential as therapeutic targets and biomarkers, although challenges in targeting circRNAs remain.