AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis through the Nrf-2/NF-κB pathway

• AKR1C3 is upregulated in hypoxic cardiomyocytes and cardiac tissue from AMI models, suggesting a protective role. • Overexpression of AKR1C3 enhances cardiomyocyte proliferation and viability, while knockdown exacerbates hypoxia-induced apoptosis. • AKR1C3 mitigates mitochondrial dysfunction by reducing ROS, preserving OCR and ATP production, and preventing apoptosis. • Mechanistically, AKR1C3 activates Nrf-2 via the ubiquitin-proteasome pathway, suppressing NF-κB and downstream Bax/caspase-3 signaling.