Journal of Inflammation Research (Dec 2024)
Maresin1 Inhibits Ferroptosis via the Nrf2/SLC7A11/GPX4 Pathway to Protect Against Sepsis-Induced Acute Liver Injury
Abstract
Yongjing Guo,1 Huimin Chen,2 Jian Sun,1 Jingxiao Zhang,1 Yongjie Yin1 1Department of Emergency and Critical Care, The Second Hospital of Jilin University, Changchun, 130021, People’s Republic of China; 2Department of Pediatric Surgery, The Second Hospital of Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Yongjie Yin, The Second Hospital of Jilin University, No. 4026, Yatai Street, Nanguan District, Changchun, 130021, People’s Republic of China, Tel +86-13756314698, Email [email protected]: Maresin 1 (MaR1) is a specialized pro-resolving mediator with anti-inflammatory properties that promotes tissue repair. This study aims to investigate the molecular involvement of MaR1 in protecting against sepsis-induced acute liver injury (SI-ALI).Methods: In vivo, a murine SI-ALI model was established using the cecal ligation and puncture (CLP) paradigm, providing a system in which the mechanistic functions of MaR1 could be tested. These analyses were supplemented through in vitro assays in which Alpha mouse liver 12 (AML12) hepatocytes and RAW264.7 macrophages were co-cultured in a Transwell system, with lipopolysaccharide (LPS) stimulation being used to establish a sepsis model. These cells were treated with MaR1 and/or nuclear factor erythroid 2-related factor 2 (Nrf2)inhibitor, while lentiviral transduction was used to knock down Nrf2 within AML12 cells. Hepatic pathological damage was assessed through hematoxylin and eosin staining. Lipid peroxidation-related analyses were conducted through the use of thiobarbituric acid, ferrous ions, glutathione, and appropriate fluorescent probes for reactive oxygen species detection. Liver enzymes and inflammatory mediators were quantified using appropriate Enzyme-Linked Immunosorbent Assays (ELISAs). Protein concentrations were evaluated via Western blot analysis.Results: The presence of ferroptosis in SI-ALI. MaR1 was found to proficiently suppress ferroptosis in SI-ALI. Mechanistically, MaR1 enhanced Nrf2 expression in AML12 hepatocytes, while the Nrf2 inhibitor ML-385 or Nrf2 siRNA mitigated MaR1’s regulatory influence on ferroptosis. Meanwhile, the expressions of the downstream genes solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) diminished, suggesting that MaR1 has a protective function via activating the Nrf2/SLC7A11/GPX4 pathway to mitigate ferroptosis in septic liver injury.Conclusion: The results indicate that MaR1 mitigates SI-ALI via stimulating the Nrf2/SLC7A11/GPX4 pathway to suppress ferroptosis. Moreover, it offers significant potential as a new agent for the prevention of SI-ALI.Keywords: Maresin1, sepsis-induced acute liver injury, ferroptosis, Nrf2, inflammation
