The Role and Mechanism of Exosome-Mediated miR-875-3p in Targeting SLC39A14 to Regulate Ferroptosis in Osteosarcoma Proliferation, Migration, and Invasion

Background Osteosarcoma is a common primary bone malignancy with a complex pathogenesis and poor prognosis. Dysregulated expression of multiple microRNAs (miRNAs) has been observed in osteosarcoma tissues and cells, where they regulate proliferation, apoptosis, invasion, and metastasis. The results reveal that miRNAs may serve as diagnostic biomarkers and therapeutic targets, providing new opportunities for early diagnosis and personalized treatment of osteosarcoma. Methods We first employed bioinformatics analyses combined with dual-luciferase reporter assays and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to identify and validate key miRNAs and mRNAs in osteosarcoma (OS). Transmission electron microscopy (TEM) and western blotting (WB) were used to explore and confirm exosomes. Lentiviral (LV) and adenoviral (ADV) transfection were applied to downregulate candidate miRNAs and mRNAs, followed by in vitro functional assays in OS cell lines. Cell viability, migration, and invasion were evaluated using CCK-8 and wound-healing assays. GSH/GSSG ratio, Fe²⁺, ROS, and MDA levels were measured with commercial kits, while RT-qPCR and WB were used to detect ferroptosis-related mRNA and protein expression. Finally, a nude mouse xenograft model was established to assess the effects of miRNA and mRNA downregulation on tumorigenesis in vivo. Results In osteosarcoma (OS) cell lines and tissues, miR-875-3p was found to be upregulated, whereas SLC39A14 was downregulated. Knockdown of miR-875-3p promoted ferroptosis and inhibited the proliferation, invasion, and migration of OS cells, while knockdown of SLC39A14 exerted the opposite effects. Moreover, RT-qPCR analysis showed a negative correlation between SLC39A14 and miR-875-3p expression, confirming their regulatory relationship. Conclusions miR-875-3p inhibits ferroptosis by downregulating SLC39A14 expression, thereby affecting the proliferation, migration, and invasion of osteosarcoma (OS) cells both in vivo and in vitro.