The role and mechanism of miR-875-3p in targeting SLC39A14 to regulate ferroptosis in osteosarcoma proliferation, migration, and invasion

BACKGROUND: Osteosarcoma is a common primary bone malignancy with poor prognosis. While microRNA dysregulation has been implicated in osteosarcoma progression, the role of exosome-mediated miRNAs, particularly miR-875-3p, in regulating ferroptosis and tumor progression remains unclear. This study aimed to investigate whether miR-875-3p promotes osteosarcoma proliferation, migration, and invasion by targeting SLC39A14 and inhibiting ferroptosis. METHODS: Exosomes were isolated from osteosarcoma tissues and H143B cells, then characterized by transmission electron microscopy as well as Western blot. Bioinformatics analysis and dual-luciferase assays identified SLC39A14 as a direct target of miR-875-3p. Lentiviral and adenoviral transfection were used to knockdown miR-875-3p and SLC39A14 in H143B cells. Cell viability, migration, and invasion were assessed using CCK-8, wound healing, and Transwell assays. Ferroptosis markers (GSH/GSSG, Fe²⁺, ROS, MDA) and related genes (GPX4, ACSL4, xCT) were eventually measured. RESULTS: Exosomes isolated from osteosarcoma tissues exhibited a typical spherical morphology and were positive for exosomal markers (HSP70, TSG101). MiR-875-3p was upregulated in osteosarcoma tissues and cell-derived exosomes, while SLC39A14 was downregulated. Knockdown of miR-875-3p upregulated SLC39A14, promoted ferroptosis, and suppressed osteosarcoma cell proliferation, migration, and invasion in vitro. In contrast, SLC39A14 knockdown attenuated ferroptosis and enhanced malignant phenotypes. In vivo, miR-875-3p knockdown inhibited tumor growth, whereas SLC39A14 knockdown promoted it. CONCLUSION: miR-875-3p promotes osteosarcoma progression by targeting SLC39A14 and suppressing ferroptosis, suggesting the miR-875-3p/SLC39A14 axis as a potential therapeutic target for osteosarcoma treatment.