COX4I1 (cytochrome c oxidase subunit 4 isoform 1) is a nuclear-encoded mitochondrial protein that functions as a critical structural and regulatory component of respiratory chain Complex IV (cytochrome c oxidase). COX4I1 is essential for the terminal step of oxidative phosphorylation, catalyzing the reduction of molecular oxygen to water while transferring electrons from cytochrome c and generating the proton gradient necessary for ATP synthesis 1. Mechanistically, COX4I1 contributes to mitochondrial Complex IV assembly and function 2. The protein regulates cellular energetics through lysine crotonylation modifications, with downregulation impairing cellular energy production and exacerbating tissue injury 3. COX4I1 expression is coordinately regulated with other mitochondrial oxidative phosphorylation genes during metabolic stress and sepsis onset 4. Additionally, COX4I1 is regulated at the transcriptional level by stress response pathways during glutamine deprivation 5. Clinically, COX4I1 mutations cause mitochondrial Complex IV deficiency, manifesting as short stature, poor weight gain, decreased COX activity, impaired ATP production, and elevated reactive oxygen species 1. COX4I1 represents a therapeutic vulnerability in acute myeloid leukemia, where depletion induces ferroptosis and synergizes with venetoclax treatment 2. The protein is also implicated in hepatocellular carcinoma progression through mitophagy regulation 6.