Academic Journal
Endogenous oxidized phospholipid POVPC triggers pulmonary epithelial ferroptosis in acute lung injury and is restrained by RCN3.
| Τίτλος: | Endogenous oxidized phospholipid POVPC triggers pulmonary epithelial ferroptosis in acute lung injury and is restrained by RCN3. |
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| Συγγραφείς: | Wang Z; Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China., Chang J; Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China., Shi X; Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China., Ding F; Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Ma RZ; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China., Wang J; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China., Ma Y; Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China., Jin J; Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. Electronic address: jiaweijin@ccmu.edu.cn. |
| Πηγή: | Free radical biology & medicine [Free Radic Biol Med] 2026 Jul; Vol. 250, pp. 189-202. Date of Electronic Publication: 2026 Mar 23. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE |
| Imprint Name(s): | Publication: Tarrytown, NY : Elsevier Science Original Publication: New York : Pergamon, c1987- |
| Ιατρικοί όροι (MeSH): | Acute Lung Injury*/pathology , Acute Lung Injury*/metabolism , Acute Lung Injury*/chemically induced , Acute Lung Injury*/genetics , Phosphatidylcholines*/metabolism , Alveolar Epithelial Cells*/metabolism , Alveolar Epithelial Cells*/pathology , Ferroptosis*, Lipopolysaccharides/toxicity ; Amino Acid Transport System y+/genetics ; Amino Acid Transport System y+/metabolism ; Epithelial Cells/metabolism ; Lung/metabolism ; Lung/pathology ; Animals ; Mice ; Mice, Knockout ; Oxidation-Reduction ; Male ; Humans ; Lipid Peroxidation ; Mice, Inbred C57BL |
| Περίληψη: | Background: Ferroptosis contributes to acute lung injury (ALI), but whether endogenous oxidized phospholipids trigger epithelial ferroptosis and which intracellular defenses restrain this process remain unclear. We hypothesized that the oxidized phosphatidylcholine POVPC initiates epithelial ferroptosis and that RCN3 functions as a protective intracellular safeguard. Methods: POVPC and PGPC were quantified in LPS-induced ALI lungs by mass spectrometry. ALI was modeled by intratracheal administration of POVPC, with equimolar PGPC as a structural control. Pulmonary epithelial cells were exposed to POVPC in vitro to assess ferroptosis. The causal role of RCN3 was investigated using AECII-specific RCN3 knockout mice and AECII-targeted AAV6-RCN3 overexpression. Results: POVPC, but not PGPC, was significantly increased in LPS-induced ALI lungs and reproduced ferroptosis-associated lung injury upon intratracheal delivery. In vitro, POVPC exposure induced pronounced ferroptosis in pulmonary epithelial cells, characterized by iron accumulation, lipid peroxidation, and depletion of GSH, GPX4, and SLC7A11, which was reversed by ferrostatin-1 and deferoxamine. POVPC elicited a transient epithelial RCN3 upregulation; however, sustained or high-dose exposure led to RCN3 exhaustion accompanied by exacerbated ferroptosis. RCN3 knockdown aggravated, whereas its overexpression attenuated, POVPC-induced ferroptosis. Consistently, AECII-specific RCN3 deletion sensitized mice to POVPC-induced ALI, while AECII-targeted AAV6-RCN3 delivery alleviated lung injury and ferroptosis. Conclusions: POVPC acts as an endogenous contributor of epithelial ferroptosis in ALI and RCN3 functions as a stress-responsive intracellular gatekeeper that limits lipid peroxidation and preserves epithelial ferroptosis resistance. (Copyright © 2026. Published by Elsevier Inc.) |
| Competing Interests: | Declaration of interests The authors declare no competing interests. |
| Contributed Indexing: | Keywords: Acute lung injury (ALI); Adeno-associated virus serotype 6 (AAV6); Ferroptosis; Glutathione peroxidase 4 (GPX4); POVPC; Pulmonary epithelial cell; Reticulocalbin 3 (RCN3); oxidized phospholipid |
| Substance Nomenclature: | 0 (Phosphatidylcholines) 0 (Lipopolysaccharides) 0 (Amino Acid Transport System y+) 0 (Slc7a11 protein, mouse) |
| Entry Date(s): | Date Created: 20260325 Date Completed: 20260713 Latest Revision: 20260713 |
| Update Code: | 20260714 |
| DOI: | 10.1016/j.freeradbiomed.2026.03.055 |
| PMID: | 41881199 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-4596 |
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| DOI: | 10.1016/j.freeradbiomed.2026.03.055 |