SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD

backgroundAcute 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.

methodsTranscriptomic analysis of ARDS datasets, LPS-induced mouse models, clinical serum samples, and LPS-stimulated AT2 cells were used to assess SERPINE1 expression. Gain- and loss-of-function approaches, ferroptosis assays, mitochondrial functional analyses, NAD

resultsSERPINE1 was markedly upregulated in ARDS patients, ARDS mouse lungs, and LPS-treated AT2 cells, correlating with disease severity. SERPINE1 deficiency or pharmacologic inhibition significantly reduced lung injury, suppressed ferroptosis markers (ACSL4, ALOX12), and restored ferroptosis-inhibitory proteins (SLC7A11, GPX4, FTH1). Mechanistically, SERPINE1 did not directly bind Sirt3, but instead interacted with complex I subunits NDUFB10 and the NAD

conclusionOur 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.