This proteomics dataset investigates the role of aquaporin-9 (AQP9) in regulating ferroptosis during myocardial ischemia-reperfusion (I/R) injury. Quantitative proteomic analysis of H9c2 cardiomyocytes (shNC controls vs shAQP9 knockdowns) was performed on a Bruker timsTOF, and AQP9 immunoprecipitation-mass spectrometry (IP-MS) was acquired on a Thermo Q Exactive HF. The data reveal that AQP9 drives ferroptotic cell death by promoting GPX4 degradation via TRIM25-mediated ubiquitination while simultaneously inhibiting GPX4 synthesis through the PI3K/AKT pathway, thereby dismantling antioxidant defenses in ischemic cardiomyocytes.