NDUFS6 promotes neuroblastoma progression and represents a potential therapeutic target

Active oxidative phosphorylation is increasingly recognized as a defining metabolic feature of high-risk neuroblastoma (NB). NDUFS6, an essential subunit of mitochondrial respiratory chain complex I, plays a critical role in sustaining oxidative phosphorylation. Nevertheless, its precise contribution to NB pathogenesis and progression remains largely undefined. We found NDUFS6 expression was significantly upregulated in high-risk NB and was positively associated with disease progression and poor prognosis. Functional assays revealed that NDUFS6 knockdown suppressed proliferation, invasion, and migration of NB cells, whereas its overexpression promoted these malignant behaviors. Transcriptomic analysis revealed that high NDUFS6 expression activated pathways related to energy metabolism and ATP synthesis, while concurrently suppressing neuronal differentiation and immune activation. Structure-based virtual screening identified several candidate inhibitors of NDUFS6, including guanosine 5′-triphosphate, 1,4-β-D-xylopentaose, and deferoxamine. Subsequent drug sensitivity assays demonstrated that guanosine 5′-triphosphate exerted potent inhibitory effects in both MYCN-amplified and non-amplified NB cell lines. These findings underscore the oncogenic role of NDUFS6 and highlight its potential as a therapeutic target for precision treatment in high-risk NB.