STUB1-mediated ubiquitination of SLC25A10 regulates mitochondrial function and drives osteosarcoma progression: A...

Osteosarcoma (OS) is a highly aggressive primary bone malignancy characterized by limited treatment options and poor clinical outcomes. Emerging evidence underscores the critical role of mitochondrial metabolism in tumor progression, positioning mitochondrial proteins as potential therapeutic targets. SLC25A10, a mitochondrial dicarboxylate carrier involved in redox homeostasis and fatty acid synthesis, has been implicated in various cancers; however, its role in OS remains unclear.In this study, we investigated the function of SLC25A10 in OS progression and its potential as a therapeutic target. Our results revealed that SLC25A10 expression is significantly upregulated in OS tissues and cell lines compared to normal bone tissue, and its elevated expression is associated with poor patient prognosis. Functional assays demonstrated that silencing SLC25A10 via shRNA or CRISPR/Cas9 significantly suppressed OS cell proliferation, migration, and mitochondrial function, resulting in mitochondrial membrane depolarization, oxidative damage, and apoptosis. In contrast, SLC25A10 overexpression promoted OS cell proliferation and migration. In vivo, knockout of SLC25A10 markedly inhibited the growth of subcutaneous OS xenografts in nude mice.Furthermore, we identified STUB1, an E3 ubiquitin ligase, as a negative regulator of SLC25A10. STUB1 knockdown reduced the ubiquitination of SLC25A10, leading to increased protein stability and elevated expression. Notably, lysine 254 (K254) was identified as a key site mediating STUB1-dependent ubiquitination of SLC25A10. STUB1-mediated downregulation of SLC25A10 suppressed OS cell proliferation and migration, indicating a tumor-suppressive role for STUB1 in OS through modulation of SLC25A10.Collectively, our findings demonstrate that SLC25A10 is essential for maintaining mitochondrial function and contributes to OS malignancy. Targeting SLC25A10 may represent a novel and promising therapeutic strategy for the treatment of osteosarcoma.