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The m 6 A eraser FTO suppresses ferroptosis via mediating ACSL4 in LPS-induced macrophage inflammation.

Authors :
Zhao Y
Ding W
Cai Y
Li Q
Zhang W
Bai Y
Zhang Y
Xu Q
Feng Z
Source :
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Oct; Vol. 1870 (7), pp. 167354. Date of Electronic Publication: 2024 Jul 14.
Publication Year :
2024

Abstract

Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m <superscript>6</superscript> A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E <subscript>2</subscript> , thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.<br />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 the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1879-260X
Volume :
1870
Issue :
7
Database :
MEDLINE
Journal :
Biochimica et biophysica acta. Molecular basis of disease
Publication Type :
Academic Journal
Accession number :
39004378
Full Text :
https://doi.org/10.1016/j.bbadis.2024.167354