Abstract
Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide, driven by complex molecular mechanisms including metabolic reprogramming and chemoresistance. Circular RNAs (circRNAs) have emerged as key regulators in cancer progression, yet their specific roles in NSCLC are underexplored. This study identified hsa_circ_103089 as a novel circRNA upregulated in NSCLC tissues and cell lines through circRNA profiling using the Gene Expression Omnibus (GEO) database. We aimed to investigate its functional roles and molecular mechanisms in NSCLC progression and cisplatin (DDP) sensitivity. Using A549 and HCC827 cell lines, we assessed the effects of hsa_circ_103089 silencing on proliferation, migration, invasion, glycolysis, and DDP resistance via techniques such as dual-luciferase reporter assays, RNA pull-down, Western blotting, and in vivo xenograft models. Results revealed that hsa_circ_103089 silencing suppressed tumor cell malignancy and glycolysis while enhancing DDP sensitivity. Mechanistically, hsa_circ_103089 acts as a sponge for miR-876-5p, upregulating EGFR expression and downstream glycolysis-related genes (e.g., LDHA, HK2, GLUT1). In vivo, hsa_circ_103089 knockdown inhibited tumor growth and potentiated DDP efficacy in nude mice. Clinically, high hsa_circ_103089 expression correlated with poor prognosis in NSCLC patients. These findings establish hsa_circ_103089 as a critical regulator of NSCLC progression and chemoresistance via the miR-876-5p/EGFR axis, highlighting its potential as a prognostic biomarker and therapeutic target.