SLC39A8 Inhibits Ferroptosis by Regulating the Β-Catenin/TCF4/ GPX4 Signaling in Osteosarcoma

SLC39A8 has been implicated in various cancers; however, its specific role in osteosarcoma (OS) remains poorly understood. This study aims to elucidate the functional significance of SLC39A8 in OS progression.

Using qRT-PCR and Western blot analysis, we analyzed SLC39A8 expression in osteosarcoma cells. Functional assays, including CCK-8, colony formation, and transwell assays, were employed to assess the impact of SLC39A8 on cell proliferation, migration, and invasion. Ferroptosis was evaluated by measuring lipid peroxidation, labile iron pool (LIP), Fe²⁷, malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), and GPX4 expression.

Our results revealed that SLC39A8 is upregulated in osteosarcoma cells. The knockdown of SLC39A8 significantly suppressed cell proliferation, migration, and invasion while inducing ferroptosis, as evidenced by increased levels of LIP, Fe²⁷, MDA, and ROS, and decreased GSH and GPX4 expression. These effects were reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Furthermore, SLC39A8 overexpression activated the Wnt/β-catenin signaling pathway and upregulated GPX4 expression, effects that were abrogated by silencing β-catenin or TCF4. In vivo experiments confirmed that SLC39A8 knockdown inhibited tumor growth.

SLC39A8 is a key zinc and iron transporter. Studies have reported that SLC39A8 was significantly dysregulated in some cancers and was associated with their prognosis. SLC39A8 has been identified as an iron metabolism- and ferroptosisrelated gene related to the prognosis of esophageal squamous cell carcinoma. Our study showed that SLC39A8 promotes osteosarcoma cell proliferation, migration, and invasion while suppressing ferroptosis by regulating β-catenin signaling. Our study further indicated that LF3 reversed SLC39A8-mediated ferroptosis in osteosarcoma cells by reducing GPX4 expression. Although our study shows that SLC39A8 regulates the β-catenin signaling pathway, the upstream regulatory mechanism remains to be investigated.

Our findings demonstrate that SLC39A8 plays a pivotal role in osteosarcoma progression by modulating ferroptosis via the β-catenin/TCF4/GPX4 signaling pathways.