Academic Journal
SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD+ homeostasis and suppressing Sirt3 activity.
| Τίτλος: | SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD+ homeostasis and suppressing Sirt3 activity. |
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| Συγγραφείς: | Gao N; China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China; Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China., Zhang WJ; China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China; Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China., Qian YX; China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China; Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China., Yang S; China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China; Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China., Zhang ZN; China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China; Graduate School, Peking University, Beijing, 100871, People's Republic of China., Lu HT; China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China; Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China., Zhang GQ; Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China. Electronic address: zhangchong2003@vip.sina.com. |
| Πηγή: | Redox biology [Redox Biol] 2026 Jul; Vol. 94, pp. 104146. Date of Electronic Publication: 2026 Apr 15. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| Ιατρικοί όροι (MeSH): | Respiratory Distress Syndrome*/metabolism , Respiratory Distress Syndrome*/pathology , Respiratory Distress Syndrome*/etiology , Respiratory Distress Syndrome*/genetics , Ferroptosis*/genetics , Mitochondria*/metabolism , Sirtuin 3*/metabolism , Sirtuin 3*/genetics , Plasminogen Activator Inhibitor 1*/metabolism , Plasminogen Activator Inhibitor 1*/genetics , NAD*/metabolism, Animals ; Mice ; Humans ; Homeostasis ; Disease Models, Animal |
| Περίληψη: | 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: Transcriptomic 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+/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: SERPINE1 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+-consuming enzyme PARP1, disrupting mitochondrial NAD+ homeostasis, decreasing the NAD+/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. (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors Declare that they have no known competing financial interests or personal relationships that could have appeared to influence that work reported in this paper. |
| Contributed Indexing: | Keywords: ARDS; Ferroptosis; Mitochondrial NAD(+)/NADH homeostasis; SERPINE1; Sirt3 |
| Substance Nomenclature: | EC 3.5.1.- (Sirtuin 3) 0 (Plasminogen Activator Inhibitor 1) 0U46U6E8UK (NAD) 0 (SERPINE1 protein, human) |
| Entry Date(s): | Date Created: 20260526 Date Completed: 20260612 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13234598 |
| DOI: | 10.1016/j.redox.2026.104146 |
| PMID: | 42190562 |
| Βάση Δεδομένων: | MEDLINE |
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