SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD+ homeostasis and suppressing Sirt3 activity

BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) is characterized by alveolar epithelial injury, inflammatory dysregulation, oxidative stress, and impaired repair capacity. Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a pathogenic driver of ARDS; however, the upstream molecular regulators that initiate ferroptotic signaling in alveolar epithelial cells remain poorly defined. SERPINE1 (PAI-1), a mediator of inflammation, coagulation dysfunction, and epithelial injury, is frequently elevated in sepsis and ARDS, yet its mechanistic role in ferroptosis remains unknown. METHODS: /NADH quantification and proteomics were performed to define the regulatory relationship between SERPINE1, Sirt3, and ferroptosis. TM5275 was used to evaluate therapeutic modulation of SERPINE1 in vivo and in vitro. RESULTS: /NADH ratio, destabilizing mitochondrial membrane potential, and suppressing Sirt3 expression. These changes amplified ferroptotic signaling under inflammatory stress. CONCLUSION: Our findings identify SERPINE1 as a previously unrecognized upstream regulator that integrates inflammatory signaling, mitochondrial redox imbalance, and ferroptosis to drive epithelial injury in ARDS. The newly defined SERPINE1-NAD/NADH-Sirt3 axis reveals a metabolically driven mechanism of ferroptosis and suggests that targeting SERPINE1 may represent a promising therapeutic strategy to mitigate ferroptosis and ameliorate lung injury.