SARS-CoV-2 ORF3a sensitizes cells to ferroptosis via Keap1-NRF2 axis

Viral infection-induced cell death has long been considered as a double-edged sword in the inhibition or exacerbation of viral infections. Patients with severe Coronavirus Disease 2019 (COVID-19) are characterized by multiple organ dysfunction syndrome and cytokine storm, which may result from SARS-CoV-2-induced cell death. Previous studies have observed enhanced ROS level and signs of ferroptosis in SARS-CoV-2 infected cells or specimens of patients with COVID-19, but the exact mechanism is not clear yet. Here, we find SARS-CoV-2 ORF3a sensitizes cells to ferroptosis via Keap1-NRF2 axis. SARS-CoV-2 ORF3a promotes the degradation of NRF2 through recruiting Keap1, thereby attenuating cellular resistance to oxidative stress and facilitated cells to ferroptotic cell death. Our study uncovers that SARS-CoV-2 ORF3a functions as a positive regulator of ferroptosis, which might explain SARS-CoV-2-induced damage in multiple organs in COVID-19 patients and imply the potential of ferroptosis inhibition in COVID-19 treatment. •Pathogenic strain of SARS-CoV-2, such as Delta, triggers the sign of ferroptosis in lung tissue of K18-hACE2 mice.•SARS-CoV-2 ORF3a sensitizes cell to ferroptosis through NRF2-ARE pathway.•SARS-CoV-2 ORF3a promotes the degradation of NRF2 via increasing the binding affinity between Keap1 and NRF2.