CISD2 promotes OS cell proliferation and migration by suppressing ferroptosis and activating the MAPK/ERK signaling pathway

Objective Osteosarcoma (OS) represents a primary bone malignancy characterized by high aggressive potential and frequent recurrence. While CDGSH iron-sulfur domain 2 (CISD2) has been implicated in diverse oncogenic processes, its precise functional involvement and regulatory pathways within the OS landscape remain largely unexplored. This investigation seeks to delineate the specific role of CISD2 in driving OS progression. Methods The study utilized clinical OS microarrays to examine CISD2 expression patterns. Through stable lentiviral-mediated knockdown and overexpression in 143B and HOS cell lines, we assessed alterations in cell viability, proliferative capacity, and motility via CCK-8, EdU, colony formation, and Transwell assays. In vivo impacts were evaluated using a BALB/c nude mouse xenograft model. Mechanistic insights were obtained through RNA-sequencing (RNA-seq) and Western blot analysis of key signaling components. Ferroptosis-related changes were evaluated by measuring intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels, together with the expression of the key ferroptosis regulators glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter xCT. Results Our analysis revealed a pronounced overabundance of CISD2 within osteosarcoma specimens and cell models relative to healthy controls. Functional assays revealed that CISD2 depletion markedly attenuated OS cell proliferation, migration, and invasion, while its overexpression elicited the opposite phenotypic effects. Furthermore, CISD2 deficiency triggered ferroptosis-characterized by elevated intracellular ROS and MDA levels alongside depleted GSH content, as well as reduced expression of GPX4 and xCT. Mechanistically, CISD2 was shown to activate the MAPK/ERK signaling axis by promoting MEK and ERK phosphorylation. Inhibiting this pathway or ferroptosis successfully reversed the cellular phenotypes induced by CISD2 modulation. Conclusion Our findings identify CISD2 as a critical oncogenic driver that promotes OS growth and metastasis by suppressing ferroptosis and activating the MAPK/ERK pathway. These results establish CISD2 as a promising diagnostic biomarker and a viable therapeutic target for osteosarcoma intervention.