NDUFB3 is an accessory subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase) that plays a critical role in electron transfer from NADH to ubiquinone during aerobic respiration 1. As a structural component essential for Complex I assembly, NDUFB3 regulates both mitochondrial respiration and reactive oxygen species (ROS) production 1. The protein can be post-translationally modified by METTL9-mediated 1-methylhistidine methylation, which enhances Complex I-dependent respiration 2. Clinically, NDUFB3 mutations cause mitochondrial complex I deficiency with variable presentations. The recurrent p.Trp22Arg variant causes a distinctive phenotype of short stature, characteristic facial features (prominent forehead, smooth philtrum, deep-set eyes), and Complex I assembly defects, though prognosis can be favorable in some cases 3. In cancer contexts, NDUFB3 exhibits dual roles: hepatocellular carcinoma cells downregulate NDUFB3 to suppress ROS-induced apoptosis and promote malignant progression 1, while thyroid and gynecological cancers show NDUFB3 upregulation associated with poor prognosis, where increased NDUFB3 elevates mitoROS levels and paradoxically suppresses tumor growth 45. Additionally, higher NDUFB3 gene expression correlates with accelerated lung function decline 6, and NDUFB3 is identified as a key lactylation-promoting gene in rheumatoid arthritis pathogenesis 7.