NDUFS3 is a core subunit of mitochondrial respiratory chain Complex I that catalyzes electron transfer from NADH through ubiquinone 12. It is essential for both Complex I catalytic activity and assembly 132. Beyond canonical respiration, NDUFS3 regulates metabolic reprogramming in disease contexts. In melanoma, elevated NDUFS3 enhances oxidative phosphorylation and the pentose phosphate pathway while suppressing glycolysis, promoting proliferation via an NDUFS3-AMPK-PRPS1 signaling axis that increases purine nucleotide synthesis 4. In sepsis-induced acute kidney injury, NDUFS3 overexpression alleviates ferroptosis and oxidative stress through AMPK pathway activation 5. Conversely, NDUFS3 downregulation is associated with poor prognosis in atherosclerosis, chr11 stress, and venous thrombosis 67, and contributes to fibrosis in benign prostatic hyperplasia 8. NDUFS3 dysfunction impairs mitochondria-lysosome crosstalk by reducing RAB7 expression, suppressing pancreatic cancer invasiveness 9. NDUFS3 is identified as a hub gene associated with mitochondrial dysfunction in myocardial infarction 10 and dysregulated glucose metabolism in polycystic ovary syndrome 11. These findings reveal context-dependent roles beyond respiratory function in cancer metabolism and metabolic diseases.