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Advanced Science

IF: 14.3
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Metabolic Interplay in Acute Lung Injury: PARK7 Integrates FADS1/2-Dependent PUFA Metabolism and H3K14 Lactylation to Attenuate Endothelial Ferroptosis and Dysfunction

Published:30 September 2025 DOI: 10.1002/advs.202508725 PMID: 41028978
Jian Xu, Yuhan Wang, Weiqi Mao, Tianchang Wei, Yufan Li, Juan Song, Cuiping Zhang, Xiaoyan Chen, Cuicui Chen, Qingyuan Xu, Xu Wu, Yuanlin Song

Abstract

Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes—downregulation of PUFA synthesis and upregulation of histone lactylation—in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI.

Substances (30)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Docosahexaenoic Acid 6217-54-5 C22H32O2 610 suppliers $16.00-$2310.00
Docosahexaenoic Acid 6217-54-5 C22H32O2 610 suppliers $16.00-$2310.00
Docosahexaenoic Acid 6217-54-5 C22H32O2 610 suppliers $16.00-$2310.00
Docosahexaenoic Acid 6217-54-5 C22H32O2 610 suppliers $16.00-$2310.00
Linolenic acid 463-40-1 C18H30O2 525 suppliers $21.00-$2506.15
Linolenic acid 463-40-1 C18H30O2 525 suppliers $21.00-$2506.15
Linolenic acid 463-40-1 C18H30O2 525 suppliers $21.00-$2506.15
Linolenic acid 463-40-1 C18H30O2 525 suppliers $21.00-$2506.15
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 247 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 247 suppliers $10.00-$2822.00

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