The m 6 A eraser FTO suppresses ferroptosis via mediating ACSL4 in LPS-induced macrophage inflammation
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 underlyi...
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Published in | Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 7; p. 167354 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
14.07.2024
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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
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
, 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. |
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AbstractList | 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
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
, 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. |
Author | Zhao, Yiqing Feng, Zhihui Zhang, Yiwen Li, Qimeng Zhang, Wenjie Cai, Yongjie Bai, Yujia Ding, Wenqian Xu, Qiong |
Author_xml | – sequence: 1 givenname: Yiqing surname: Zhao fullname: Zhao, Yiqing email: zhaoyq25@mail2.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: zhaoyq25@mail2.sysu.edu.cn – sequence: 2 givenname: Wenqian surname: Ding fullname: Ding, Wenqian email: dingwq3@mail2.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: dingwq3@mail2.sysu.edu.cn – sequence: 3 givenname: Yongjie surname: Cai fullname: Cai, Yongjie email: caiyj23@mail2.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: caiyj23@mail2.sysu.edu.cn – sequence: 4 givenname: Qimeng surname: Li fullname: Li, Qimeng organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China – sequence: 5 givenname: Wenjie surname: Zhang fullname: Zhang, Wenjie email: zhangwj233@mail2.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: zhangwj233@mail2.sysu.edu.cn – sequence: 6 givenname: Yujia surname: Bai fullname: Bai, Yujia email: baiyj23@mail2.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: baiyj23@mail2.sysu.edu.cn – sequence: 7 givenname: Yiwen surname: Zhang fullname: Zhang, Yiwen organization: Peking University Shenzhen Hospital, Shenzhen 518036, China – sequence: 8 givenname: Qiong surname: Xu fullname: Xu, Qiong email: xqiong@mail.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: xqiong@mail.sysu.edu.cn – sequence: 9 givenname: Zhihui surname: Feng fullname: Feng, Zhihui email: fengzhh8@mail.sysu.edu.cn organization: Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China. Electronic address: fengzhh8@mail.sysu.edu.cn |
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Keywords | FTO Acute lung injury Ferroptosis ACSL4 Inflammation Macrophage |
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Title | The m 6 A eraser FTO suppresses ferroptosis via mediating ACSL4 in LPS-induced macrophage inflammation |
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