Neddylation inhibition extends lifespan and preserves cardiac function during aging via mitophagy

Age-related cardiac dysfunction is closely linked to impaired mitophagy and mitochondrial quality control. Here, we identify neddylation inhibition as a previously unrecognized strategy to activate mitophagy and improve cardiac function during aging. Using high-content screening of ~10,000 compounds, we uncovered MLN4924, a clinically advanced neddylation inhibitor, as a potent inducer of mitophagy across diverse systems. MLN4924 enhanced mitophagic flux in human iPSC-derived cardiomyocytes and mouse hearts via a non-canonical pathway that bypasses PINK1/Parkin and mitochondrial fission. Mechanistically, MLN4924 stabilized HIF1α by disrupting CUL2-mediated degradation, leading to upregulation of the mitophagy receptor BNIP3. In aged mice, late-life MLN4924 treatment restored cardiac mitophagy, reversed ventricular hypertrophy, and improved diastolic function. MLN4924 also extended lifespan in C. elegans, underscoring the systemic benefit of neddylation blockade. These findings establish neddylation as a druggable regulator of mitochondrial quality control and aging, offering a potential therapeutic framework to combat age-related cardiac decline.