Med1 inhibits ferroptosis and alleviates liver injury in acute liver failure via Nrf2 activation

• Published in: Cell & bioscience Vol. 14; no. 1; pp. 54 - 18
• Main Authors: Lei, Zi-Ying, Li, Zhi-Hui, Lin, Deng-Na, Cao, Jing, Chen, Jun-Feng, Meng, Shi-Bo, Wang, Jia-Lei, Liu, Jing, Zhang, Jing, Lin, Bing-Liang
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.04.2024; BioMed Central; BMC
• Subjects: Acute liver failure; Antioxidants; Cell death; Ferroptosis; Genes; Glutamate; Health aspects; Heme; Heme oxygenase-1; Interleukins; Ligases; Liver failure; Mediator complex subunit 1; NAD(P)H quinone oxidoreductase 1; Nuclear factor erythroid 2-related factor 2; Prognosis; Tumor necrosis factor; China; Acute liver failure; Ferroptosis; Heme oxygenase-1; NAD(P)H quinone oxidoreductase 1; Mediator complex subunit 1; Nuclear factor erythroid 2-related factor 2
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-024-01234-4

Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H O or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF.